3,3-Biarylpiperidine and 2,2-biarylmorpholine derivatives

ABSTRACT

The present invention relates to compounds of the formula I,  
                 
 
     wherein Z 1 , Z 2 , X, Q, R 1 , R 2  and R 3  are defined as in the specification, pharmaceutical compositions containing such compounds the use of such compounds to treat neurological and gastrointestinal disorders.

BACKGROUND OF THE INVENTION

[0001] This invention relates to 3,3-biarylpiperidine and2,2-biarylmorpholine derivatives which have utility as ligands foropioid receptors.

[0002] In the study of opioid biochemistry, a variety of endogenousopioid compounds and non-endogenous opioid compounds has beenidentified. In this effort, significant research has been focused onunderstanding the mechanism of opioid drug action, particlarly as itrelates to cellular and differentiated tissue opioid receptors.

[0003] Opioid drugs are typically classified by their bindingselectivity in respect of the cellular and differentiated tissuereceptors to which a specific drug species binds as a ligand. Thesereceptors include mu (μ), delta (δ) and kappa (κ) receptors.

[0004] At least three subtypes of opioid receptors (mu, delta and kappa)are described and documented in the scientific literature. All threereceptors are present in the central and peripheral nervous systems ofmany species including man. Activation of delta receptors producesantinociception in rodents and can induce analgesia in man, in additionto influencing motility of the gastrointestinal tract. (See Burks, T. F.(1995) in “The Pharmacology of Opioid Peptides”, edited by Tseng, L. F.,Harwood Academic Publishers).

[0005] The well known narcotic opiates such as morphine and its analogsare selective for the opioid mu receptor. Mu receptors mediateanalgesia, respiratory depression, and inhibition of gastrointestinaltransit. Kappa receptors mediate analgesia and sedation.

[0006] The existence of the opioid delta receptor is a relatively recentdiscovery which followed the isolation and characterization ofendogenous enkephalin peptides, which are ligands for the deltareceptor. Research in the past decade has produced significantinformation about the delta receptor, but a clear picture of itsfunction has not yet emerged. Delta receptors mediate analgesia, but donot appear to inhibit intestinal transit in the manner characteristic ofmu receptors.

[0007] U.S. Pat. No. 4,816,586, which issued on Mar. 28, 1989 to P. S.Portoghese, refers to various delta opioid receptor antagonists. Thesecompounds are described as possessing a unique opioid receptorantagonist profile, and include compounds that are highly selective forthe delta opioid receptor.

[0008] U.S. Pat. No. 4,518,711, which issued May 21, 1985 to V. J. Hrubyet al., describes cyclic, conformationally constrained analogs ofenkephalins. These compounds include both agonists and antagonists forthe delta receptor, and are said to induce pharmacological andtherapeutic effects, such as analgesia in the case of agonist species ofsuch compounds. The antagonist species of the disclosed compounds aresuggested to be useful in the treatment of schizophrenia, Alzheimer'sdisease, and respiratory and cardiovascular functions.

[0009] S. Goenechea, et al, in “Investigation of the Biotransformationof Meclozine in the Human Body,” J. Clin. Chem. Clin. Biochem., 1988,26(2), 105-15, describe the oral administration of a polyaryl piperazinecompound in a study of meclozine metabolization in human subjects.

[0010] In “Plasma Levels, Biotransformation and Excretion of Oxatomidein Rats, Dogs, and Man,” Xenobiotica, 1984, 15(6), 445-62, Meuldermans,W., et al., refer to a metabolic study of plasma levels,biotransformation, and excretion of oxatomide.

[0011] T. Iwamoto, et al, in “Effects of KB-2796, A New CalciumAntagonist, and Other Diphenylpiperazines on [³H]nitrendipine Binding”,Jpn. J Pharmacol., 1988, 48(2), 241-7, describe the effect of a polyarylpiperazine as a calcium antagonist.

[0012] K. Natsuka, et al, in “Synthesis and Structure-ActivityRelationships of 1-Substituted 4-(1,2-Diphenylethyl)piperazineDerivatives Having Narcotic Agonist and Antagonist Activity,” J. Med.Chem., 1987, 30 (10), 1779-1787, disclose racemates and enantiomers of1-substituted 4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazinederivatives.

[0013] European Patent Application No. 458,160, published on Nov. 27,1991, refers to certain substituted diphenylmethane derivatives asanalgesic and antiinflammatory agents, including compounds wherein themethylene bridging group (linking the two phenyl moieties) issubstituted on the methylene carbon with a piperidinyl or piperazinylgroup.

[0014] South African Patent Application No. 8604522, which was publishedon Dec. 12, 1986, refers to certain N-substituted arylalkyl andaryl-alkylene substituted amino-heterocyclic compounds, includingpiperdine derivatives, as cardiovascular, antihistamine, andanti-secretory agents.

[0015] European Patent Application No. 133,323, published on Feb. 20,1985, refers to certain diphenylmethyl piperazine compounds asnon-sedative antihistamines.

[0016] There is a continuing need in the art for improved opioidcompounds, particularly compounds which are free of addictive characterand other adverse side effects of conventional opiates such as morphineand pethidine.

[0017] The present inventor has discovered a novel class of3,3-biarylpiperidine and morpholine derivatives that are potent andselective delta opioid ligands and are useful for treatment of rejectionin organ transplants and skin grafts, epilepsy, chronic pain, neurogenicpain, nonsomatic pain, stroke, cerebral ischemica, shock, head trauma,spinal cord trauma, brain edema, Hodgkin's disease, Sjogren's disease,systemic lupus erythematosis, gastrointestinal disorders such asgastritis, functional bowel disease, irritable bowel syndrome,functional diarrhoea, functional distention, nonulcerogenic dyspepsiaand other disorders of motility or secretion, and emesis, acute pain,chronic pain, neurogenic pain, nonsomatic pain, allergies, respiratorydisorders such as asthma, cough and apnea, inflammatory disorders suchas rheumatoid arthritis, osteoarthristis, psoriasis and inflammatorybowel disease, urogenital tract disorders such as urinary incontinence,hypoxia (e.g., perinatal hypoxia), hypoglycemic neuronal damage,chemical dependencies and addictions (e.g., a dependency on, oraddiction to opiates, benzodiazepines, cocaine, nicotine or ethanol),drug or alcohol withdrawal symptoms, and cerebral deficits subsequent tocardiac bypass surgery and grafting.

SUMMARY OF THE INVENTION

[0018] This invention relates to compounds of the formula

[0019] wherein R¹ is hydrogen, (C₀-C₈)alkoxy-(C₁-C₈)alkyl-, wherein thetotal number of carbon atoms is eight or less, aryl, aryl-(C₁-C₈)alkyl-,heteroaryl, heteroaryl-(C₁-C₈)alkyl-, heterocyclic,heterocyclic-(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl-, or(C₃-C₇)cycloalkyl-(C₁-C₈)alkyl, wherein said aryl and the aryl moiety ofsaid aryl-(C₁-C₈)alkyl- are selected, independently, from phenyl andnapthyl, and wherein said heteroaryl and the heteroaryl moiety of saidheteroaryl-(C₁-C₈)alkyl- are selected, independently, from pyrazinyl,benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl,pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl,1,2,5-thiadiazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl,phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl,5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolyl, oxadiazolyl,isoxazoyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl,tetrazolyl, triazolyl, thienyl, imidazolyl, pyridinyl, and pyrimidinyl;and wherein said heterocyclic and the heterocyclic moiety of saidheterocyclic-(C₁-C₈)alkyl- are selected from saturated or unsaturatednonaromatic monocyclic or bicyclic ring systems, wherein said monocyclicring systems contain from four to seven ring carbon atoms, from one tothree of which may optionally be replaced with O, N or S, and whereinsaid bicyclic ring systems contain from seven to twelve ring carbonatoms, from one to four of which may optionally be replaced with O, N orS; and wherein any of the aryl, heteroaryl or heterocyclic moieties ofR¹ may optionally be substituted with from one to three substitutuents,preferably with one or two substutituents, independently selected fromhalo (i.e., chloro, fluoro, bromo or iodo), (C₁-C₆)alkyl optionallysubstituted with from one to seven (preferably with from zero to four)fluorine atoms, phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro,(C₁-C₆)alkoxy, (C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂amino, and whereinany of the alkyl moieties in R¹ (e.g., the alkyl moieties of alkyl,alkoxy or alkylamino groups) may optionally be substituted with from oneto seven (preferably with from zero to four) fluorine atoms;

[0020] R² is hydrogen, aryl, heteroaryl, heterocyclic, SO₂R⁴, COR⁴,CONR⁵R⁶, COOR⁴, or C(OH)R⁵R⁶ wherein each of R⁴, R⁵ and R⁶ is defined,independently, as R¹ is defined above, or R⁵ and R⁶, together with thecarbon or nitrogen to which they are both attached, form a three toseven membered saturated ring containing from zero to threeheterocarbons selected, independently, from O, N and S, and wherein saidaryl, heteroaryl, and heterocyclic are defined as such terms are definedabove in the definition of R¹, and wherein any of the aryl, heteroaryland heterocyclic moieties of R² may optionally be substituted with fromone to three substitutuents, preferably with one or two substutituents,independently selected from halo (i.e., chloro, fluoro, bromo or iodo),(C₁-C₆)alkyl optionally substituted with from one to seven (preferablywith from zero to four) fluorine atoms, phenyl, benzyl, hydroxy, acetyl,amino, cyano, nitro, (C₁-C₆)alkoxy optionally substituted with from oneto seven (preferably with from zero to four) fluorine atoms,(C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂amino;

[0021] R³ is hydroxy, —NHSO₂R⁷, —C(OH)R⁷R⁸, —OC(═O)R⁷, fluorine or—CONHR⁷, wherein R⁷ and R⁸ are the same or different and are selectedfrom hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and(C₁-C₄)alkoxy-(C₁-C₄)alkyl having a total of four or less carbon atoms,and wherein any of the alkyl moieties of R⁷ and R⁸ may optionally besubstituted with from one to seven (preferably with from zero to four)fluorine atoms;

[0022] Q is oxygen or CH₂;

[0023] X is CH or N; and

[0024] Z¹ and Z² are selected, independently, from hydrogen, halo and(C₁-C₅)alkyl;

[0025] with the proviso that there are no two adjacent ring oxygen atomsand no ring oxygen atom adjacent to either a ring nitrogen atom or aring sulfur atom in any of the heterocyclic or heteroaryl moieties offormula I;

[0026] and the pharmaceutically acceptable salts of such compounds.

[0027] Preferred compounds of the formula I include those wherein Q isCH₂.

[0028] Other preferred compounds of the formula I are those wherein X isCH.

[0029] Other preferred compounds of the formula I are those wherein R³is OH, CONH₂, or fluoro.

[0030] Other preferred compounds of the formula I are those wherein R²is selected from C(OH)(C₂H₆)₂, CON(C₂H₆)₂, CONCH₃(C₂H₆) and thefollowing cyclic groups:

[0031] Other preferred compounds of the formula I are those wherein Z¹and Z² are selected, independently, from hydrogen and fluorine.

[0032] Other preferred compounds of the formula I are those wherein R¹is selected from allyl, cyclopropylmethyl, methyl, 2,2,2-trifluoroethyl,methallyl, isopropyl, 2-pyridinyl, 2-pyrimidinyl and

[0033] Examples of other embodiments of the present invention are thefollowing:

[0034] compounds of the formula I wherein Q is oxygen and X is CH;

[0035] compounds of the formula I wherein Q is oxygen and X is N;

[0036] compounds of the formula I wherein Q is oxygen, X is CH and R³ isOH, CONH₂, or fluoro;

[0037] compounds of the formula I wherein Q is oxygen and X is N;

[0038] compounds of the formula I wherein Q is CH₂, X is N, and R³is OH,CONH₂, or fluoro;

[0039] compounds of the formula I wherein Q is CH₂, X is N, R³ is OH,CONH₂, or fluoro, and R² is selected from C(OH)(C₂H₆)₂, CON(C₂H₆)₂ andone of cyclic groups (a)-(f) depicted above; and

[0040] compounds of the formula I wherein Q is oxygen, X is CH, and R³is OH, CONH₂, or fluoro;

[0041] compounds of the formula I wherein Q is oxygen, X is NH, R³ isOH, CONH₂, or fluoro, and R² is selected from C(OH)(C₂H₆)₂, CON(C₂H₆)₂and one of cyclic groups (a)-(f) depicted above;

[0042] compounds of the formula I wherein Q is oxygen, X is CH, R³ isOH, CONH₂ or fluoro, Z¹ and Z² or selected, independently, from hydrogenand fluoro, and R¹ is selected from allyl, cyclopropylmethyl, methyl,methalyl, isopropyl, 2-pyridinyl, 2-pyrimidinyl and cyclic group (g)depicted above; and

[0043] compounds of the formula I wherein Q is oxygen, X is NH, R³ isOH, CONH₂ or fluoro, Z¹ and Z² or selected, independently, from hydrogenand fluoro, and R¹ is selected from allyl, cyclopropylmethyl, methyl,methalyl, isopropyl, 2-pyridinyl, 2-pyrimidinyl and cyclic group (g)depicted above.

[0044] The compounds of formula I and their pharmaceutically acceptablesalts are opioid receptor ligands and are useful in the treatment of avariety of neurological and gastrointestinal disorders. Examples ofdisorders that can be treated with the compounds of formula I and theirpharmaceutically acceptable salts are rejection in organ transplants andskin grafts, epilepsy, chronic pain, neurogenic pain, nonsomatic pain,stroke, cerebral ischemica, shock, head trauma, spinal cord trauma,brain edema, Hodgkin's disease, Sjogren's disease, systemic lupuserythematosis, gastrointestinal disorders such as gastritis, functionalbowel disease, irritable bowel syndrome, functional diarrhoea,functional distention, nonulcerogenic dyspepsia and other disorders ofmotility or secretion, and emesis, acute pain, chronic pain, neurogenicpain, nonsomatic pain, allergies, respiratory disorders such as asthma,cough and apnea, inflammatory disorders such as rheumatoid arthritis,osteoarthritis, psoriasis and inflammatory bowel disease, urogenitaltract disorders such as urinary incontinence, hypoxia (e.g., perinatalhypoxia), hypoglycemic neuronal damage, chemical dependencies andaddictions (e.g., a dependency on, or addiction to opiates,benzodiazepines, cocaine, nicotine or ethanol), drug or alcoholwithdrawal symptoms, and cerebral deficits subsequent to cardiac bypasssurgery and grafting.

[0045] The present invention also relates to the pharmaceuticallyacceptable acid addition and base addition salts of compounds of theformula I. The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the aforementioned base compounds ofthis invention are those which form non-toxic acid addition salts, i.e.,salts containing pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts. The chemical basesthat are used as reagents to prepare the pharmaceutically acceptablebase salts of this invention are those which form non-toxic base saltswith the acidic compounds of formula I. Such non-toxic base saltsinclude those derived from such pharmacologically acceptable cations assodium, potassium, calcium and magnesium, etc.

[0046] The present invention also relates to the pharmaceuticallyacceptable base addition salts of compounds of the formula I. Thesesalts are all prepared by conventional techniques. The chemical basesthat are used as reagents to prepare the pharmaceutically acceptablebase salts of this invention are those which form non-toxic base saltswith the acidic compounds of formula I. Such non-toxic base saltsinclude those derived from such pharmacologically acceptable cations assodium, potassium, calcium and magnesium, etc.

[0047] For a review on pharmaceutically acceptable salts, see Berge etal., J. Pharm. Sci., 66, 1-19 (1977).

[0048] This invention also relates to a pharmaceutical composition fortreating a disorder or condition, the treatment or prevention of whichcan be effected or facilitated by modulating (i.e., increasing ordecreasing) binding to opioid receptors in a mammal, including a human,comprising an amount of a compound of the formula I, or apharmaceutically effective salt thereof, that is effective in treatingsuch disorder or condition and a pharmaceutically acceptable carrier.

[0049] This invention also relates to a method of treating a disorder orcondition, the treatment of which can be effected or facilitated bymodulating binding to opioid receptors in a mammal, comprisingadministering to a mammal in need of such treatment an amount of acompound of the formula I, or a pharmaceutically effective salt thereof,that is effective in treating such disorder or condition.

[0050] This invention also relates to a pharmaceutical composition fortreating a disorder or condition selected from inflammatory diseasessuch as arthritis (e.g., rheumatoid arthritis and osteoarthritis),psoriasis, asthma, or inflammatory bowel disease, disorders ofrespiratory function such as asthma, cough and apnea, allergies,gastrointestinal disorders such as gastritis, functional bowel disease,irritable bowel syndrome, functional diarrhoea, functional distension,functional pain, nonulcerogenic dyspepsia and other disorders ofmotility or secretion, and emesis, stroke, shock, brain edema, headtrauma, spinal cord trauma, cerebral ischemia, cerebral deficitssubsequent to cardiac bypass surgery and grafting, urogential tractdisorders such as urinary incontinence, chemical dependencies andaddictions (e.g., addictions to or dependencies on alcohol, opiates,benzodiazepines, nicotine, heroin or cocaine), chronic pain, nonsomaticpain, acute pain and neurogenic pain, systemic lupus erythematosis,Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organtransplants and skin grafts in a mammal, including a human, comprising aglutamate neurotransmission modulating effective amount of a compound ofthe formula I, or a pharmaceutically salt thereof, and apharmaceutically acceptable carrier.

[0051] This invention also relates to a method for treating a conditionselected from inflammatory diseases such as arthritis, psoriasis,asthma, or inflammatory bowel disease, disorders of respiratory functionsuch as asthma, cough and apnea, allergies, gastrointestinal disorderssuch as gastritis, functional bowel disease, irritable bowel syndrome,functional diarrhoea, functional distension, functional pain,nonulcerogenic dyspepsia and other disorders of motility or secretion,and emesis, stroke, shock, brain edema, head trauma, spinal cord trauma,cerebral ischemia, cerebral deficits subsequent to cardiac bypasssurgery and grafting, urogential tract disorders such as urinaryincontinence, chemical dependencies and addictions (es, addictions to ordependencies on alcohol, opiates, benzodiazepines, nicotine, heroin orcocaine), chronic pain, nonsomatic pain, acute pain and neurogenic pain,systemic lupus erythematosis, Hodgkin's disease, Sjogren's disease,epilepsy and rejection in organ transplants and skin grafts, in amammal, comprising administering to such mammal, including a human, anopioid receptor binding modulating effective amount of a compound of theformula I, or a pharmaceutically acceptable salt thereof.

[0052] This invention also relates to a pharmaceutical composition fortreating a disorder or condition, the treatment of which can be effectedor facilitated by modulating binding to opioid receptors in a mammal,including a human, comprising an opioid receptor binding modulatingeffective amount of a compound of the formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

[0053] This invention also relates to a method for treating a disorderor condition, the treatment of which can be effected or facilitated bymodulating in a mammal, including a human, comprising administering tosuch mammal an opioid receptor binding modulating effective amount of acompound of the formula I or a pharmaceutically acceptable salt thereof.

[0054] This invention also relates to a method of treating a conditionselected from inflammatory diseases such as arthritis, psoriasis,asthma, or inflammatory bowel disease, disorders of respiratory functionsuch as asthma, cough and apnea, allergies, gastrointestinal disorderssuch as gastritis, functional bowel disease, irritable bowel syndrome,functional diarrhoea, functional distension, functional pain,nonulcerogenic dyspepsia and other disorders of motility or secretion,and emesis, stroke, shock, brain edema, head trauma, spinal cord trauma,cerebral ischemia, cerebral deficits subsequent to cardiac bypasssurgery and grafting, urogential tract disorders such as urinaryincontinence, chemical dependencies and addictions (e.g., addictions toor dependencies on alcohol, opiates, benzodiazepines, nicotine, heroinor cocaine), chronic pain, nonsomatic pain, acute pain and neurogenicpain, systemic lupus erythematosis, Hodgkin's disease, Sjogren'sdisease, epilepsy and rejection in organ transplants and skin grafts ina mammal, comprising administering to a mammal in need of such treatmentan amount of a compound of the formula I that is effective in treatingsuch condition.

[0055] This invention also relates to a pharmaceutical composition fortreating a condition selected from inflammatory diseases such asarthritis, psoriasis, asthma, or inflammatory bowel disease, disordersof respiratory function such as asthma, cough and apnea, allergies,gastrointestinal disorders such as gastritis, functional bowel disease,irritable bowel syndrome, functional diarrhoea, functional distension,functional pain, nonulcerogenic dyspepsia and other disorders ofmotility or secretion, and emesis, stroke, shock, brain edema, headtrauma, spinal cord trauma, cerebral ischemia, cerebral deficitssubsequent to cardiac bypass surgery and grafting, urogential tractdisorders such as urinary incontinence, chemical dependencies andaddictions (e.g., addictions to or dependencies on alcohol, opiates,benzodiazepines, nicotine, heroin or cocaine), chronic pain, nonsomaticpain, acute pain and neurogenic pain, systemic lupus erythematosis,Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organtransplants and skin grafts in a mammal, comprising an amount of acompound of the formula I that is effective in treating such conditionand a pharmaceutically acceptable carrier.

[0056] Unless otherwise indicated, the alkyl groups referred to herein,as well as the alkyl moieties of other groups referred to herein (e.g.,alkoxy), may be linear or branched, and they may also be cyclic (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear orbranched and contain cyclic moieties.

[0057] The term “alkoxy”, as used herein, means “-O-alkyl”, wherein“alkyl” is defined as above.

[0058] The term “alkylene”, as used herein, means an alkyl group havingtwo available binding sites (i.e., -alkyl-, wherein alkyl is defined asabove).

[0059] The term “treating” as used herein, refers to reversing,alleviating, inhibiting the progress of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treatment”, as used herein, refers tothe act of treating, as “treating” is defined immediately above.

[0060] Unless otherwise indicated, “halo” and “halogen”, as used herein,refer to fluorine, bromine, chlorine or iodine.

[0061] Compounds of the formula I may have chiral centers and thereforemay exist in different enantiomeric and diastereomic forms. Thisinvention relates to all optical isomers and all other stereoisomers ofcompounds of the formula I, and to all racemic and other mixturesthereof, and to all pharmaceutical compositions and methods of treatmentdefined above that contain or employ such isomers or mixtures.

[0062] Formula I above also includes isotopically labelled compoundsthat are identical to those depicted in formula I, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Certain isotopicallylabelled compounds of the present invention, for example, those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. Tritiated,i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferredfor their ease of preparation and detectability. Further, substitutionwith heavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Isotopically labelledcompounds of formula I of this invention can generally be prepared bycarrying out the procedures disclosed in the schemes and/or in theExamples below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

DETAILED DESCRIPTION OF THE INVENTION

[0063] The compounds of formula I can be prepared according to themethods illustrated in Schemes 1-9 and discussed below. In the reactionschemes and discussion that follow, unless otherwise indicated, X, Q, Y,Z¹, Z², R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ and structural formula I aredefined as above.

[0064] Scheme 1 illustrates a method for the preparation of compoundswith the general formula I wherein R³ is (C₁-C₆)alkoxy or fluorine, R²is CONR⁵R⁶, Y is carbon, Q is carbon, X is carbon and R¹ is as definedabove with the proviso that it is not attached to the piperidinenitrogen at a secondary alkyl carbon or an aryl group. Referring toScheme 1, a bromobenzene derivative of formula 0, wherein R³ is methoxyor fluorine, is cooled to −70° C. in dry tetrahydrofuran, and then asolution of n-butyllithium is added to it. The resulting solution isthen treated with N-benzylpiperidin-3-one and the solution is allowed towarm to room temperature to produce the corresponding compound offormula 1.

[0065] Alternatively, the benzene derivative of formula 0 intetrahydrofuran can be treated with magnesium at a temperature fromabout 0° C. to the reflux temperature, preferably starting at roomtemperature for about three hours and then heating to reflux and lettingthe reaction proceed for another hour, after whichN-benzylpiperidin-3-one is added to the mixture. The resulting solutionis then stirred at a temperature ranging from about 0° C. to the refluxtemperature, preferably at about room temperature, to produce thecorresponding compound of formula 1.

[0066] The compound of formula 1, produced by either of the abovemethods, in dichloroethane is then treated with phenol and aluminumchloride or another Lewis acid (e.g., zinc chloride, boron trifluorideetherate), and the resulting solution is stirred at a temperatureranging from about 0° C. to the reflux temperature, preferably at aboutthe reflux temperature, to produce the corresponding phenol derivativeof formula 2. The compound of formula 2 is then treated withtrifluoromethane sulfonic anhydride or another suitable reagent such asN-phenyltrifluoromethanesulfonimide, in the presence of a base such aspyridine, triethylamine, another trialkyl amine, an alkali metal hydrideor an alkali metal carbonate, to form the trifluoromethane sulfonateester of formula 3. This reaction is typically performed indicloromethane at a temperature ranging from about 0° C. to the refluxtemperature, preferably at about room temperature.

[0067] The compound of formula 3 is placed under a carbon monoxideatmosphere at a pressure ranging from about 14 to 100 psi, in a solutionof dimethylsulfoxide and a lower alkanol such as methanol or ethanol,with a suitable trialkylamine base (e.g., triethylamine) and palladiumacetate with 1,3-bis(diphenylphosphino)propane (DPPP),1,3-bis(diphenylphosphino)-ferrocene (DPPF) or another suitablepalladium ligand. Other suitable palladium catalysts such asbis(triphenylphosphine) palladium dichloride may also be used. Thisreaction is performed at temperatures ranging from about 20° C. to 100°C.

[0068] Treatment of the ester of formula 4 with an aluminum amide of aprimary or secondary amine, for example, diethyl amine, in a solventsuch as dichloroethane or toluene, at a temperature ranging from about20° C. to about the reflux temperature, preferably at about the refluxtemperature, yields the corresponding amide of formula 5. Variations inthe nature of the R¹ group on the piperidine nitrogen can be effected inthe following manner, as illustrated by process steps (5→6→7) inScheme 1. The compound of formula 5 is placed under a hydrogenatmosphere at pressures ranging from about 14 to 100 psi, in ethanol orother another solvent such as acetic acid or methanol, to produce thecorresponding compound of formula 6. This reaction is typically carriedout at a temperature from about 0° C. to about the reflux temperature,preferably at about room temperature.

[0069] Treatment of the compound of formula 6 with an aldehyde andsodium triacetoxyborohydride or another reducing agent (e.g., sodiumborohydride or sodium cyanoborohydride), in dicloromethane, 1,2dichloroethane or another suitable solvent such as methanol, ethanol ortoluene, at a temperature ranging from about 0° C. to 100° C.,preferably at about room temperature, yields the desired compound offormula 7.

[0070] Compounds of formula I wherein R¹ is a group that attaches to thepiperidine nitrogen via an aryl moiety or a primary or secondary alkylmoiety, can be prepared by treating the corresponding compound offormula 6 with an alkylating or arylating agent of the formula R¹X,wherein X is a leaving group such as chloro, bromo, iodo, triflate(OTf), mesylate (OMs) or tosylate (Ots), and sodium or potassiumcarbonate or another alkali metal carbonate or bicarbonate in a solventsuch as dimethylformamide, dichloromethane or 1,2 dichloroethane, at atemperature ranging from about 20° C. to 100° C., as shown below inScheme 2.

[0071] Compounds of the general formula I where R³ is hydroxy can beprepared by deprotecting the corresponding alkyl ether of formula 7(wherein R¹⁰ is (C₁-C₆)alkyl) with boron tribromide in dicloromethane,or with aqueous hydrobromic acid and acetic acid, or with sodiumethanethiolate in dimethylformamide, at a temperature ranging from about0° C. to the reflux temperature, as shown in Scheme 3. Room temperatureis preferred when boron tribromide is used, the reflux temperature ispreferred when hydrobromic acid/acetic acid is used, and about 100° C.to about 120° C. is preferred when sodium ethanmethiolate is used.

[0072] The carboxarnide of formula 12 can be obtained by conversion thephenol of formula 9 in to triflate ester of formula 10 with the additonof triflic anhydride in the presence of a base such as pyridine, or atrialkylamine base like triethylamine, and in the presence ofdimethylamino pyridine in a solvent such as methylene chloride, at atemperature ranging from −40° C. to the reflux temperature, preferablyat 0° C.. The triflate ester of formula 10 is then converted into thenitrile of formula 11 by treatment with zinc cyanide and a palladiumcatalyst such as tetrakis triphenylphosphine palladium, in a solventsuch as dimethylformamide, or toluene, at a temperature from about 0° C.to about the reflux temperature, preferably at about the refluxtemperature. The nitrile of formula 11 can be converted into thecarboxamide of formula 12 by treatment with hydrogen peroxide and sodiumcarbonate in ethanol, at a temperature ranging from about 0° C. to aboutthe reflux temperature, preferably at about room temperature.

[0073] Compounds of the general formula I wherein R³ is methoxy, hydroxyor fluorine and R² is an aromatic or heteroaromatic moiety (referred toin Scheme 5 as compounds of the formula 14) can be prepared byorganometalic coupling of a compound of the formula 3 with an aryl andheteroaryl boronic acid, wherein aryl and heteroaryl are defined as inthe definitions of R¹ and R², in a solvent such as ethanol or toluene,in the presence of a of palladium catalyst such as tetrakistriphenylphosphine palladium and a trialkylamine base (e.g.,triethylamine) or alkali metal carbonate base, as shown below in Scheme5. This reaction is generally carried out at a temperature from aboutroom temperature to about the reflux temperature, preferably at aboutthe reflux temperature.

[0074] Compounds of the general formula I where R³ is fluoro or methoxyand R² is a carbinol such as diethyl carbinol (referred to in Scheme 6as compounds of the formula 15) can be prepared, as illustrated inScheme 6 by treatment of the ester of formula 4 with an alkyl Grignardor alkyl lithium reagent, in a solvent such as ether or tetrahydrofuran,at a temperature ranging from about −78° C. to about the refluxtemperature, preferably starting at room temperature and heating toabout the reflux temperature.

[0075] Compounds of the formulas 14 (Scheme 5) and 15 (Scheme 6) can beconverted into the analogous compounds wherein R³=CONH₂ using theprocedures illustrated in Schemes 3 and 4 and described above forsynthesizing carboxamides of the formula 12.

[0076] Compounds of the general formula 16 can be prepared, asillustrated in Scheme 7, by treatment of the phenol of formula 9 with anacid chloride, in the presence of pyridine or a trialkylamine such astriethylamine in dichloromethane, tetrahydrofuran or another suitablesolvent, at a temperature ranging from about −78° C. to about the refluxtemperature, preferably at room temperature.

[0077] Scheme 8 illustrates a method for preparing compounds of thegeneral formula I wherein Q is oxygen, R³ is methoxy, hydroxy, R² isCONR⁵R⁶ and R¹ is as defined above. Referring to Scheme 8, abromobenzene derivative of formula 17, wherein R³ is methoxy orfluorine, is cooled to −70° C. in dry tetrahydrofuran, and treated witha solution of n-butyllithium. The resulting solution is then treatedwith an appropriately substituted aryl aldehyde of the formula 18, andthe solution is allowed to warm to room temperature to produce thecorresponding compound of formula 19.

[0078] Alternatively, the benzene derivative of formula 17 intetrahydrofuran can be treated with magnesium at a temperature fromabout 0° C. to about the reflux temperature, preferably starting at roomtemperature for about three hours and then heating to reflux and lettingthe reaction proceed for about another hour, after which the arylaldehyde of formula 18 is added to the mixture. The resulting solutionis then stirred at a temperature ranging from about 0° C. to the refluxtemperature, preferably at about room temperature, to produce thecorresponding compound of formula 19.

[0079] Compounds of the formula 20 can be prepared using a Swernoxidation. Thus, a solution of trifluroacetic anhydride in methylenechloride is treated with DMSO at a temperature from about −78° C. toabout room temperature, preferably at −78° C., and to this mixture isadded a solution of the compound of formula 19 in methylene chloride,followed by addition of a trialkylamine base such as triethylamine. Themixture is allowed to warm to room temperature to produce thecorresponding compound of the formula 20. Alternatively, compounds ofthe formula 20 can be prepared by oxidation of the compound of formula19 by addition of pyridinium dichromate, in a solvent such as methylenechloride, at a temperature from about −78° C. to about the refluxtemperature, preferably at about room temperature.

[0080] Compounds of the formula 20 can be converted into compounds offormula 21 via addition of trimethylsilyl cyanide in the presence ofzinc iodide in a solvent such as methylene chloride, at a temperaturefrom about −78° C. to about the reflux temperature, preferably at aboutroom temperature, followed by treatment of the intermediate cyanohydrinewith lithium aluminum hydride or another metal hydride source such asdiisobutyl aluminum hydride, in a solvent such as methylene chloride, ata temperature from about −78° C. to about the reflux temperature,preferably at 0° C.

[0081] Treatment of a compound of the formula 21 with a trialkylaminebase such as triethylamine and chloroacetylchloride in a solvent such astoluene or tetrahydrofuran, at a temperature ranging from about −40° C.to about the reflux temperature, preferably at 0° C., yields thecorresponding compound having formula 22. Subsequent treatment of adilute solution of the resulting compound of formula 22 in a solventsuch as tetrahydrofuran or toluene with metal alkoxides, preferablypotasium t-butoxide, at a temperature ranging from about −40° C. toabout the reflux temperature, preferably at about room temperature,affords the corresponding derivative of formula 23. Reaction of thederivative of formula 23 with lithium aluminum hydride or another metalhydride source such as dibutyl aluminum hydride, in a solvent such asmethylene chloride, at a temperature from about −78° C. to about thereflux temperature, preferably at about 0° C., affords the correspondingcompound of formula 24.

[0082] When R¹ is not attached to the morpholine nitrogen at a secondaryalkyl carbon or an aryl group, the R¹ group can be added to themorpholine nitrogen of the compound of formula 24 by reacting suchcompound with an aldehyde and sodium triacetoxyborohydride or anotherreducing agent (e.g., sodium borohydride or sodium cyanoborohydride) indicloromethane, 1,2 dichloroethane or another suitable solvent such asmethanol, ethanol or toluene, at a temperature ranging from about 0° C.to 100° C., preferably at about room temperature. This reaction yieldsthe desired compound of formula 25. When R¹ is attached to themorpholine nitrogen via an aryl moiety or a primary or secondary alkylmoiety, it can be added to the compound of formula 24 using theprocedure illustrated in Scheme 2 and described above. Compounds of theformula 25 can be produced by alkylation or heteroarylation of thecorresponding compound of formula 24 using conditions identical to thosedescribed above for the preparation of compounds of the formula 7 Scheme2.

[0083] The compound of formula 25 is then placed under a carbon monoxideatmosphere at a pressure ranging from about 14 to 100 psi, in a solutionof dimethylsulfoxide and a lower alkanol such as methanol or ethanol,with a suitable trialkylamine base (e.g., triethylamine) and palladiumacetate with 1,3-bis(diphenylphosphino)propane (DPPP) or anothersuitable palladium ligand, to yield the desired compound of formula 26.Other suitable palladium catalysts, such as bis(triphenylphosphine)palladium dichloride, may also be used. This reaction can be conductedat temperatures ranging from about 20° C. to about 100° C., preferablyat about 70° C. Treatment of the ester of formula 26 with an aluminumamide of a primary or secondary amine, for example, diethyl amine, in asolvent such as dichloroethane or toluene, at a temperature ranging fromabout 20° C. to about the reflux temperature, preferably at about thereflux temperature, yields the corresponding amide of formula 27.

[0084] Compounds of the formula 28 where R³ is hydroxy can be preparedby deprotecting the corresponding alkyl ethers of formula 27 (wherein R³is OR¹⁰ and R¹⁰ is (C₁-C₆)alkyl) with boron tribromide indicloromethane, or with aqueous hydrobromic acid and acetic acid, orwith sodium ethanethiolate in dimethylformamide, at a temperatureranging from about 0° C. to the about reflux temperature, as illustratedin Scheme 3. Room temperature is preferred when boron tribromide isused, the reflux temperature is preferred when hydrobromic acid/aceticacid is used, and about 100° C. to about 120° C. is preferred whensodium ethanethiolate is used.

[0085] Compounds of the formula 25 can be converted into thecorresponding compounds wherein the bromine substituent is replaced byan aromatic or heteroaromatic substituent using the procedureillustrated in Scheme 5 and discussed above. Compounds of the formula 26can be converted into the corresponding compounds wherein R² is—C(OH)R⁵R⁶ rather than —COOR⁷ using the procedure described above andillustrated in Scheme 6. Compounds of the formula 28 can be derivatizedto form the corresponding compounds wherein R³ is —CONH₂ and —OC(═O)R⁷using the procedures described above and illustrated in Schemes 4 and 7,respectively, for preparing compounds of the formula 12 (Scheme 4) and16 (Scheme 7).

[0086] Scheme 9 illustrates a method for the preparation of compoundswith the general formula I wherein X is nitrogen, R³ is methoxy,hydroxy, R² is CONR⁵R⁶ and R¹ is as defined above. Referring to Scheme9, compounds of the formula 31 can be obtained by the treatment ofphenyl acetonitrile derivatives of the formula 29 with sodium hydrideand a 2-bromopyridine or 2-halopyridine derivative of the formula 30 indimethylformamide or in another suitable solvent such astetrahydrofuran, at a temperature from about 0° C. to about the refluxtemperature, preferably at about 60° C.

[0087] Treatment of compounds of the formula 31 with sodium hydride indimethylformamide or another suitable solvent such as tetrahydrofuran,at a temperature from about 0° C. to about the reflux temperature,preferably at 60° C., followed by the treatment with a alkylating agentsuch as 1-bromo-3-chloropropane, at a temperature from about 0° C. toabout the reflux temperature, preferably at about 60° C., yields thecorresponding compounds of formula 32.

[0088] Reduction of the cyano group of compounds of the formula 32 witha reducing agent such as diisobutyl aluminum hydride or another reducingmetal hydride source such as lithum aluminum hydride, in a solvent suchas methylene chloride, at a temperature from about −78° C. to about thereflux temperature, preferably at about −78° C., and warming graduallyto room temperature, affords the corresponding compounds of formula 33after vigorous stirring in a saturated aqueous Rochelle's salt solution.

[0089] When R¹ does not attach to the piperidine nitrogen at an arylmoiety or secondary alkyl carbon, compounds of the formula 33 can beconverted into the corresponding compounds of formula 34 by reactingthem with an aldehyde and sodium triacetoxyborohydride or anotherreducing agent (e.g., sodium borohydride or sodium cyanoborohydride), indicloromethane, 1,2 dichloroethane or another suitable solvent such asmethanol, ethanol or toluene, at a temperature ranging from about 0° C.to about 100° C., preferably at about room temperature. When R¹ attachesto the piperidine nitrogen via an aryl moiety or a primary or secondaryalkyl carbon, compounds of the formula 34 can be produced by alkylationor heteroarylation of compounds of the general formula 33 usingconditions identical to those described for the preparation of compoundsof the formula 7 in Scheme 2.

[0090] The compounds of formula 34 are then placed under a carbonmonoxide atmosphere at a pressure ranging from about 14 to 100 psi, in asolution of dimethylsulfoxide and a lower alkanol such as methanol orethanol, with a suitable trialkylamine base (e.g., triethylamine) andpalladium acetate with 1,3-bis(diphenylphosphino)propane (DPPP) oranother suitable palladium ligand. Other suitable palladium catalystssuch as bis(triphenylphosphine) palladium dichloride may also be used.This reaction, which is typically conducted at temperatures ranging fromabout 20° C. to about 100° C., yields the desired compound of formula35.

[0091] Treatment of the ester of formula 35 with an aluminum amide of aprimary or secondary amine, for example, diethyl amine, in a solventsuch as dichloroethane or toluene, at a temperature ranging from about20° C. to about the reflux temperature, preferably at about the refluxtemperature, yields the corresponding amide of formula 36.

[0092] Compounds of the formula 37 wherein R³ is hydroxy can be preparedby deprotecting the corresponding alkyl ethers of formula 36 (wherein R³is OR¹⁰ and R¹⁰ is (C₁-C₆)alkyl) with boron tribromide indicloromethane, or with aqueous hydrobromic acid and acetic acid, orwith sodium ethanethiolate in dimethylformamide, at temperatures rangingfrom about 0° C. to about the reflux temperature, as shown in Scheme 3.Room temperature is preferred when boron tribromide is used, the refluxtemperature is preferred when hydrobromic acid/acetic acid is used, andabout 100° C. to about 120° C. is preferred when sodium ethanmethiolateis used.

[0093] Compounds of the formula 34 can be converted into thecorresponding compounds wherein the bromine substituent is replaced byan aromatic or heteroaromatic substituent using the procedureillustrated in Scheme 5 and discussed above. Compounds of the formula 35can be converted into the corresponding compounds wherein R² is—C(OH)R⁵R⁶ rather than —COOR⁷ using the procedure described above andillustrated in Scheme 6. Compounds of the formula 37 can be derivatizedto form the corresponding compounds wherein R³ is —CONH₂ and —OC(═O)R⁷using the procedures described above and illustrated in Schemes 4 and 7,respectively, for preparing compounds of the formula 12 (Scheme 4) and16 (Scheme 7).

[0094] Scheme 10 illustrates a method for preparing compounds of thegeneral formula I wherein R³ is NHSO₂R⁷. Referring to Scheme 10, thephenol of formula 38 is converted into the triflate of formula 39 by theprocedures illustrated in Schemes 1 and 4 and described above, afterwhich the triflate is transformed into the ester of formula 40 by theprocedure illustrated in Scheme 1 and described above. The ester offormula 40 can then be converted into the carboxylic acid of formula 41by hydrolyzing it with lithium hydroxide in a water/THF solution atabout room temperature. Treatment of the resulting carboxlic acid offormula 41 with diphenylphosphoryl azide and triethylamine in atert-butanol solvent at about the reflux temperature yields thecorresponding tert-butyl carbamate of formula 42. Acidic treatment ofthe carbamate of formula 42 with trifluoroacetic acid in methylenechloride yields the corresponding aniline of formula 43. The aniline offorumla 43 can then be reacted with sulfonyl chloride, in the presenceof a base such as pyridine or triethylamine, to yield the desiredsulfonamide of formula I. This reaction is preferrable carried out in apolar solvent such as methylene chloride, dicloroethane or THF, at atemperature from about 0° C. to about the reflux temperature of thesolvent.

[0095] The preferred method of making compounds of the formula I whereinR³ is OH, NHSO₂R⁷, C(OH)R⁷R⁸ or C(═O)NHR⁷ is to make the analogouscompounds wherein R³ is O—(C₁-C₆)alkyl and then derivatize them usingstandards methods well known in art and illustrated in the foregoingschemes.

[0096] The starting materials used in the processes of Schemes 1-9 areeither commercially available, known in the literature, or readilyobtainable from commercially available or known compounds using methodsthat are well known in the art or described above.

[0097] Unless indicated otherwise, the pressure of each of the abovereactions is not critical. Generally, the reactions will be conducted ata pressure from about one to about three atmospheres, preferably atambient pressure (about one atmosphere).

[0098] The preparation of other compounds of the formula I notspecifically described in the foregoing experimental section can beaccomplished using combinations of the reactions described above thatwill be apparent to those skilled in the art.

[0099] The compounds of the formula I that are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. The acid that can be used to prepare thepharmaceutically acceptable acid addition salts of the base compounds ofthis invention are those which form non-toxic acid addition salts, i.e.,salts containing pharmacologically acceptable anions, such ashydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate,phosphate or acid phosphate, acetate, lactate, citrate or acid citrate,tartrate or bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate and pamoate [i.e.,,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts. Although such saltsmust be pharmaceutically acceptable for administration to animals, it isoften desirable in practice to initially isolate a compound of theformula I from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent, and subsequently convert the freebase to a pharmaceutically acceptable acid addition salt. The acidaddition salts of the base compounds of this invention are readilyprepared by treating the base compound with a substantially equivalentamount of the chosen mineral or organic acid in an aqueous solventmedium or in a suitable organic solvent such as methanol or ethanol.Upon careful evaporation of the solvent, the desired solid salt isobtained.

[0100] Compounds of the formula that are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations.These salts are all prepared by conventional techniques. The chemicalbases that are used as reagents to prepare the pharmaceuticallyacceptable base salts of this invention are those which form non-toxicbase salts with the acidic compounds of formula I. Such non-toxic basesalts include those derived from such pharmacologically acceptablecations as sodium, potassium, calcium and magnesium, etc. These saltscan easily be prepared by treating the corresponding acidic compoundswith an aqueous solution containing the desired pharmacologicallyacceptable cations, and then evaporating the resulting solution todryness, preferably under reduced pressure. Alternatively, they may alsobe prepared by mixing lower alkanolic solutions of the acidic compoundsand the desired alkali metal alkoxide together, and then evaporating theresulting solution to dryness in the same manner as before. In eithercase, stoichiometric quantities of reagents are preferably employed inorder to ensure completeness of reaction and maximum yields of thedesired final product.

[0101] The compounds of the formula I and the pharmaceuticallyacceptable salts thereof (hereinafter, also referred to, collectively,as “the active compounds of the invention”) are useful for the treatmentof neurodegenerative, psychotropic and drug or alcohol induced deficitsand are potent opioid receptor ligands. The active compounds of theinvention may therefore be used in the treatment of disorders andconditions, such as those enumerated above, that can be treated bymodulatiing binding to an opioid receptor.

[0102] The ability of the compounds of formula I to bind to the variousopioid receptors and their functional activity at such receptors can bedetermined as described below. Binding to the delta opioid receptor canbe determined using procedures well known in the art, such as thosereferred to by Lei Fang et al., J. Pharm. Exp. Ther., 268, 1994, 836-846and Contreras et al., Brain Research, 604, 1993,160-164.

[0103] In the description of binding and functional assays that follows,the following abbreviations and terminology are used.

[0104] DAMGO is [D-Ala2,N-MePhe4,Gly5-ol]enkephalin).

[0105] U69593 is ((5a, 7a,8b)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxasipro[4,5]dec-8-yl)-benzeneacetamide).

[0106] SNC-80 is(+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide.

[0107] nor BNI is nor-binaltorphimine.

[0108] CTOP is 1,2-Dithia-5,8,11,14,17-pentaazacycloeicosane, cyclicpeptide derivative DPDPE is [D-en2,D-Pen5]enkephalin).

[0109] [3H]-DAMGO, [3H]-U69593, norBNI, and CTOP are all commerciallyavailable from DuPont, Amersham International, RBI and DuPont, AmershamInternational, RBI and DuPont respectively.

[0110] [3H]-SNC80 was prepared by Amersham International.

[0111] Opioid (mu and kappa) receptor binding assays can be performed inguinea-pig brain membrane preparations. Binding assays can be carriedout at 25° C. for 60 minutes in 50 mM Tris (pH 7.4) buffer. [³H]-DAMGO(2nM) and [³H]-U-69,593 (2 nM) can be used to label mu and kappa receptorbinding sites, respectively. The protein concentration can beapproximately 200 μg/well. Non-specific binding can be defined with 10μM naloxone.

[0112] Delta receptor binding assays can be performed in a stable lineof CHO cells expressing the human delta receptor. The binding assay canbe carried out at 25° C. for 120 minutes in 50 mM Tris (pH 7.4) buffer.[³H]-SNC-80 can be used to label delta receptor binding sites. Theprotein concentration can be approximately 12.5 μg/well. Non-specificbinding can be defined with 10 μM naltrexone.

[0113] The binding reaction can be terminated by rapid filtrationthrough glass fibre filters, and the samples can be washed with ice-cold50 mM Tris buffer (pH 7.4).

[0114] Agonist activity at the delta, mu and kappa opioid receptors canbe determined as follows.

[0115] Opioid (delta, mu and kappa) activity is studied, as describedbelow, in two isolated tissues, the mouse deferens (MVD)(δ) and theguinea-pig myentric plexus with attached longitudinal muscle (GPMP) (μand k).

[0116] MVD (DC1 strain, Charles River, 25-35 g) are suspended in 15 mlorgan baths containing Mg⁺⁺ free Krebs' buffer of the followingcomposition (mM): NaCl, 119; KCl, 4.7; NaHCO₃, 25; KH₂PO₄, 1.2; CaCl₂,2,5 and glucose, 11. The buffer is gassed with 95% O₂ and 5% CO₂. Thetissues are suspended between platinum electrodes, attached to anisometric transducer with 500 mg tension and stimulated with 0.03 Hzpulses of 1-msec pulse-width at supramaximal voltage. IC₅₀ values aredetermined by the regression analysis of concentration-response curvesfor inhibition of electrically-induced contractions in the presence of300 nM of the mu-selective antagonist CTOP. This test is a measure of δagonism.

[0117] Guinea-pig (Porcellus strain, male, 450-500 g, Dunkin Hartley)myentric plexus with attached longitudinal muscle segments are suspendedwith 1 g of tension in Krebs' buffer and stimulated with 0.1 Hz pulsesof 1-msec pulse-width at supramaximal voltage. Mu functional activity isdetermined in the presence of 10 nM nor-BNI with 1 μM of the muselective agonist, DAMGO, added to the bath at the end of the experimentto define a maximal response. This test is a measure of mu agonism.

[0118] Kappa functional activity is determined in the presence of and 1μM CTOP with 1 μM of the kappa selective agonist U-69,593 added at theend of the experiment to define a maximal response. All inhibitions oftwitch height for test compounds are expressed as a percentage of theinhibition obtained with the standard agonist and the corresponding IC₅₀values determined.

[0119] The following procedure can be used to determine the activity ofthe therapeutic agents of this invention as agonists and as antagonistsof delta opioid receptors.

[0120] Cell Culture: Chinese hamster ovary cells expressing the humandelta opioid receptor are passaged twice weekly in Hamis F-12 media withL-glutamine containing 10% fetal bovine serum and 450 μg/mL hygromycin.Cells are prepared for assays 3 days prior to the experiment. 15 mL of0.05% trypsin/EDTA is added to a confluent triple flask, swirled anddecanted to rinse. 15 mL of 0.05% trypsin/EDTA is again added, and theflask is placed into a 37C incubator for 2 minutes. Cells are removedfrom the flask by banking, and supernatant poured off into a 50 mL tube.30 mL of media is then added to the flask to stop the action of thetrypsin, and then decanted into the 50 mL tube. Tube is then centrifugedfor 5 minutes at 1000 rpm, media decanted, and the pellet resuspendedinto 10 mL of media. Viability of the cells is assessed using trypanblue, the cells counted and plated out into 96 well poly-D-lysine coatedplates at a density of 7,500 cells/well.

[0121] Antagonist Test Plate: Cells plated 3 days prior to assay arerinsed twice with PBS. The plates are placed into a 37C water bath. 50μL of assay buffer (PBS, dextrose 1 mg/mL, 5 mM MgC12, 30 mM HEPES, 66.7μg/mL of IBMX) is then added to designated wells. Fifty microliters ofappropriate drug is then added to designated wells, and timed for 1minute. Fifty microliters of 10 μM forskolin+0.4 nM DPDPE (final assayconcentration is 5 μM forskolin, 0.2 nM DPDPE) is then added toappropriate wells, and timed for 15 minutes. The reaction is stopped bythe addition of 10 μL of 6N perchloric acid to all wells. To neutralize,13 82 L of 5N KOH is added to all wells, and to stabilize 12 μL of 2MTris, pH 7.4 is added to all wells. Mix by shaking on an orbital shakerfor 10 minutes, and centrifuge at setting 7 for 10 minutes. Alliquotinto 3H plate.

[0122] Agonist Test Plate: Cells plated 3 days prior to assay are rinsedtwice with PBS. The plates are placed into a 37° C. water bath. Fiftymicroliters of assay buffer (PBS, dextrose 1 mg/mL, 5 mM MgCl₂, 30 mMHEPES, 66.7 μg/mL of IBMX) is then added to designated wells. Fiftymicroliters of appropriate drug+10 μM forskolin (final assayconcentration is 5 μM forskolin) is then added to all wells, and timedfor 15 minutes. The reaction is then stopped by the addition of 10 μL of6N perchloric acid to all wells. To neutralize, 13μ of 5N KOH is addedto all wells, and to stablize 12 μL of 2M Tris, pH 7.4 is added to allwells. Mix by shaking on an orbital shaker for 10 minutes, andcentrifuge at setting 7 for 10 minutes. Alliquot into 3H plate.

[0123] Both test plates are placed into an Amersham 3H cAMP binding kitovernight, and harvested onto GF/B filters previously soaked in 0.5% PEIwith a Skatron using 50 mM Tris HCl pH 7.4 at 4° C. Filtermats can beair-dried overnight then place in bags with 20 ml Betaplatescintillation cocktail and counted on a Betaplate counter for 60 sec persample. Data can be analyzed using Excel.

[0124] The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, transdermal (e.g., patch), intranasal, parenteral(e.g., intravenous, intramuscular or subcutaneous) or rectaladministration or in a form suitable for administration by inhalation orinsufflation.

[0125] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycollate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (es,almond oil, oily esters or ethyl alcohol); and preservatives (e.g.,methyl or propyl p-hydroxybenzoates or sorbic acid).

[0126] For buccal administration the composition may take the form oftablets or lozenges formulated in conventional manner.

[0127] The active compounds of the invention may be formulated forparenteral administration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

[0128] The active compounds of the invention may also be formulated inrectal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides.

[0129] For intranasal administration or administration by inhalation,the active compounds of the invention are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insulator may be formulated containing a powder mixof a compound of the invention and a suitable powder base such aslactose or starch.

[0130] In general, a therapeutically effective daily oral or intravenousdose of the compounds of formula (I) and their salts is likely to rangefrom 0.001 to 50 mg/kg body weight of the subject to be treated,preferably 0.1 to 20 mg/kg. The compounds of the formula (I) and theirsalts may also be administered by intravenous infusion, at a dose whichis likely to range from 0.001-10 mg/kg/hr.

[0131] Tables or capsules of the compounds may be administered singly ortwo or more at a time as appropriate. It is also possible to administerthe compounds in sustained release formulations.

[0132] The physician will determine the actual dosage which will be mostsuitable for an individual patient and it will vary with the age, weightand response of the particular patient. The above dosages are exemplaryof the average case. There can, of course, be individual instances wherehigher or lower dosage ranges are merited, and such are within the scopeof this invention.

[0133] Alternatively, the compounds of the formula (I) can beadministered by inhalation or in the form of a suppository or pessary,or they may be applied topically in the form of a lotion, solution,cream, ointment or dusting powder. An alternative means of transdermaladministration is by use of a skin patch. For example, they can beincorporated into a cream consisting of an aqueous emulsion ofpolyethylene glycols or liquid paraffin. They can also be incorporated,at a concentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstablisers and preservatives as may be required.

[0134] The following Examples illustrate the preparation of thecompounds of the present invention. Commercial reagents were utilizedwithout further purification. All NMR data were recorded at 250, 300 or400 MHz in deuterochloroform unless otherwise specified and are reportedin parts per million (δ) and are referenced to the deuterium lock signalfrom the sample solvent. All non-aqueous reactions were carried out indry glassware with dry solvents under an inert atmosphere forconvenience and to maximize yields. All reactions were stirred with amagnetic stirring bar unless otherwise stated. Unless otherwise stated,all mass spectra were obtained using chemical impact conditions. Ambientor room temperature refers to 20-25° C.

EXAMPLE 1N,N-DIETHYL-4-[3-(3-METHOXY-PHENYL)-PIPERIDIN-3-YL]-1-BENZAMIDE

[0135] A. 1-Benzyl-3-(3-methoxy-phenyl)-piperidin-3-ol

[0136] To a suspension of magnesium (7.8 g, 325 mmol) in THF (120 mL) atroom temperature under a nitrogen atmosphere was added a solution of3-bromoanisole (37.5 mL, 296 mmol) in THF (60 mL) over 10 min. Theresulting mixture was stirred at 50° C. for 4 hours and was cooled toroom temperature. To the mixture was added a solution anN-benzyl-3-piperidinone (30.0 g, 159 mmol) in THF (50 mL). The reactionwas stirred at room for 10 hours. The mixture was poured slowly overice-water (100 mL) and the aqueous layer was washed with EtOAc (3×50mL). The combined organic extracts were dried (MgSO₄) and concentrated.The crude residue was purified by flash chromatography withhexanes/EtOAc (3:1) to afford 38.4 g of1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-ol ¹HNMR (400 MHz, CDCl₃) δ7.31-7.20 (comp, 6H), 7.09 (s, 1H), 7.01 (d, 1H), 6.79 (d, 1H),4.01-3.96 (br, 1H), 3.79 (s, 3H), 3.58 (s, 2H), 2.91 (d, 1H), 2.74 (d,1H), 2.32 (d, 1H), 2.09-1.82 (comp, 2H), 1.81-1.61 (comp, 3H); MS (M+1)298.2.

[0137] B. 4-[1-Benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenol

[0138] To a solution of 1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-ol(17.6 g, 73.1 mmol) in (CH₂)₂Cl₂ (200 mL) was added phenol (16.7 g, 178mmol) followed by portionwise addition (highly exothermic) of AlCl₃(23.3 g, 178 mmol). The reaction mixture was heated to reflux for 2hours. The mixture was cooled to room temperature and was slowly pouredinto a mixture of crushed ice (50 mL) and 30% aq. NH₄OH (120 mL). Themixture was stirred vigorously for 20 mininutes and was then filteredthrough celite. The celite cake was washed with CH₂Cl₂ (200 mL). Theorganic layer was separated and the aqueous layer was washed with CH₂Cl₂(3×100 mL). The combined organic layers were dried (MgSO₄) andconcentrated. The crude residue was purified by flash chromatographywith hexanes/EtOAc (1:1) to afford 16.3 g of4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenol ¹HNMR (400 MHz,CDCl₃) 6 7.39-7.21 (comp, 5H), 7.19-7.05 (comp. 3H), 6.84 (s, 1H), 6.79(d, 1H), 6.67-6.61 (comp, 3H), 3.73 (s, 3H), 3.50 (s, 2H), 2.86-2.79(comp, 2H), 2.45-2.38 (comp, 2H), 2.21-2.19 (comp, 2H), 1.60-1.51 (comp,2H); MS (M+1) 374.2.

[0139] C. Trifluoro-methanesulfonic Acid4-[l-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl ester

[0140] To a slurry of4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenol (10.4 g, 27.8mmol) in CH₂Cl₂ (60 mL) at 0° C. was added pyridine (3.37 mL, 41.7 mmol)followed by dropwise addition of triflic anhydride (5.62 mL, 27.8 mmol)over 5 minutes. The reaction mixture was stirred at 0° C. for 1 hour andat room temperature for 2 hours. The solution was then cooled to 0° C.and 40 mL of cold saturated aqueous NaHCO₃ were added. The organic layerwas separated and the aqueous layer was washed with CH₂Cl₂ (3×50 mL).The combined organic layers were dried (MgSO₄) and concentrated. Thecrude residue was purified by flash chromatography with hexanes/EtOAc(4:1) to afford 9.81 g of Trifluoro-methanesulfonic acid4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl ester. ¹HNMR(400 MHz, CDCl₃) δ 7.39-7.22 (comp, 7H), 7.15 (t, 1H), 7.09 (d, 2H),6.76-6.67 (comp, 3H), 3.72 (s, 3H), 3.52-3.49 (comp, 2H), 3.08-2.91 (m,1H), 2.2.72-2.60 (m, 1H), 2.59-2.49 (m, 1H), 2.41-2.29 (m, 1H),2.23-2.19 (comp, 2H), 1.61-1.41 (comp, 2H); MS (M+1) 506.1.

[0141] D. 4-[1-Benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-benzoic acidmethyl ester

[0142] To a solution of trifluoro-methanesulfonic acid4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl ester (12.9 g,25.4 mmol) in a Parr pressure bottle in MeOH (39 mL) were added DMSO (18mL) and triethylamine (21 mL, 151 mmol). To the reaction mixture wereadded palladium acetate (3.99 g, 17.8 mmol) and 1,3-bis(diphenylphosphino) propane (5.25 g, 12.3 mmol). The mixture was shakenunder 40 psi of CO at 70° C. for 4 hours. The reaction mixture wascooled to room temperature and was diluted with diethyl ether (600 mL).The ether layer was washed with water (5×60 mL), dried (MgSO₄) andconcentrated. The crude residue was purified by flash chromatographywith hexanes/EtOAc (3:1) to afford 9.82 g of4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-benzoic acid methylester. ¹HNMR (400 MHz, CDCl₃) δ 7.87 (d, 2H), 7.41-7.20 (comp, 7H), 7.12(t, 1H), 6.77 (s, 1H), 6.73 (d, 1H), 6.66 (d, 1H), 3.86 (s, 3H), 3.71(s, 3H), 3.51 (s, 2H), 3.05 (br, 1H), 2.68 (br, 1H), 2.55 (br, 1H),2.41-2.24 (comp, 2H), 2.22-2.18 (m, 1H) 1.61-1.42 (comp, 2H); MS (M+1)416.3.

[0143] E.4-[1-Benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0144] To a solution of diethyl amine (8.21 mL, 79.6 mmol) in CH₂ClCH₂Cl(20 mL) at room temperature was added a trimethylaluminum (39.8 mL, 79.6mmol, 2M in hexanes) dropwise. The reaction mixture was stirred at roomtemperature for 1 hour. A solution of4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-benzoic acid methylester (6.0 g, 14.5 mmol) in (CH₂)₂Cl₂ (6 mL) was added and the reactionmixture was heated to reflux for 14 hours (h). The solution was thencooled 0° C. and sat. aqueous sodium bicarbonate (NaHCO₃) (15 mL) wasadded dropwise. The mixture was filtered through celite. The celite cakewas washed with CH₂Cl₂ (40 mL). The organic layer was separated and theaqueous layer was washed with CH₂Cl₂ (3×30 mL). The combined organiclayers were dried over magnesium sulfate (MgSO₄) and concentrated. Thecrude residue was purified by flash chromatography with ethyl acetate(EtOAc) to afford 6.57 g of4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.41-7.20 (comp, 9H), 7.14 (t, 1H), 6.82 (s,1H), 6.75 (d, 1H), 6.66 (d, 1H), 3.73 (s, 3H), 3.68-3.51 (comp, 2H),3.50 (s, 2H), 3.32-3.21 (comp, 2H), 2.98-2.89 (m, 1H), 2.82-2.74 (m,1H), 2.65-2.59 (m, 1H), 2.56-2.32 (comp, 2H), 2.29-2.19 (comp, 3H),1.57-1.49 (comp, 1H), 1.23-1.10 (comp, 3H), 1.09-1.04 (comp, 2H); MS(M+1) 457.3.

[0145] F. N,N-Diethyl-4-[3-(3-methoxy-phenyl)-piperidin-3-yl]-benzamide

[0146] To a solution of4-[1-benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamidein acetic acid (8 mL) in a Parr pressure bottle was added palladiumhydroxide (Pd(OH)₂) (10% on carbon, 0.4 g). The reaction mixture wasshaken under 50 psi of H₂ for 20 hours. The reaction mixture was thenfilterd through celite. The celite cake was washed withEtOAdDiethyl-4-[3-(3-methoxy-phenyl)-piperidin-3-yl]-benzamide as theacetate salt. ¹HNMR (400 MHz, CDCl₃) δ 7.39-7.17 (comp, 5H), 6.84-6.61(comp, 3H), 3.74 (s, 3H), 3.73-3.60 (comp, 2H), 3.57-3.41 (comp, 2H),3.38-3.14 (comp, 2H), 3.11-2.89 (comp, 2H), 2.48-2.26 (comp, 2H),1.81-1.66 (comp, 2H), 1.21-1.70 (comp, 3H), 1.06-0.99 (comp, 3H); MS(M+1) 367.4.

[0147] The following compounds were made using the procedure set forthabove in Example 1, starting with a compound analogous to the titlecompound of Example 1A wherein R³ is fluoro or methoxy, and adding theappropriate amine reactant in the procedure of Example 1E.

[0148] 4-[1-Benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N-ethyl-N-methyl-benzamide

[0149]¹HNMR (400 MHz, CDCl₃) δ 7.31 (d, 4H), 6.82 (s, 1H), 6.76 (d, 2H),6.67 (dd, 1H), 3.71 (s, 3H), 3.53 (br, 1H), 3.50 (s, 2H), 3.27 (br, 1H),2.25-2.21 (comp, 2H); MS (M+1) 443.3.

[0150]4-[1-Benzyl-3-(3-fluoro-5-methoxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0151]¹HNMR (400 MHz, CDCl₃) δ 7.33-7.29 (comp, 4H), 7.25-7.21 (comp,5H), 6.59 (s, 1H), 6.54 (d, 1H), 6.39 (dt, 1H), 3.69 (s, 3H), 3.54-3.45(comp, 4H), 3.24 (br, 2H), 2.80 (br, 2H); MS (M+1) 475.3.

[0152]4-[1-Benzyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N-(2,2,2-trifluoro-ethyl)-benzamide

[0153]¹HNMR (400 MHz, CDCl₃) δ 7.64 (d, 2H), 6.76-6.66 (comp, 3H), 6.30(br, 1H), 4.11-4.07 (comp, 2H), 3.51 (s, 2H), 2.24-2.19 (comp, 1H), MS(M+1) 483.3.

EXAMPLE 2 GENERAL PROCEDURE FOR THE REDUCTIVE ALKYLATION OFN,N-DIETHYL-4-[3-(3-METHOXY-PHENYL)-PIPERIDIN-3-YL]-BENZAMIDE

[0154] To a solution ofN,N-diethyl-4-[3-(3-methoxy-phenyl)-piperidin-3-yl]-benzamide (1equivalent) in methylene chloride (CH₂Cl₂) (0.4M) was added the aldehyde(1.2 equivalents) followed by addition of acetic acid (1.2 equivalents)and NaBH(OAc)₃ (1.5 equivalents). The reaction mixture was stirred atroom temperature for 16 hours. The mixture was then partitioned betweenequal volumes of CH₂Cl₂ and sat. aqueous sodium bicarbonate (NaHCO₃).The organic layer was separated and the aqueous layer was washed withCH₂Cl₂ (3×). The combined organic layers were dried (MgSO₄) andconcentrated. Purification by flash chromatography afforded the desiredtertiary amines in yields ranging from 60-95%.

[0155] The following compounds were made using a procedure similar tothat of Example 2, starting with a diarylsubstituted pyridine wherein R³is fluoro or methoxy and R² is the appropriate amide group.

[0156]4-[1-Cyclopropylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0157]¹HNMR (400 MHz, CDCl₃) δ 7.34 (d, 2H), 7.24 (dd, 2H), 7.13 (t,1H), 6.91 (s, 1H), 6.84 (d, 1H), 6.66 (dd, 1H), 3.71 (s, 3H), 3.48 (br,2H), 3.25 (br, 2H), 3.05-2.80 (comp, 2H), 2.48 (br, 2H), 2.29-2.20(comp, 4H), 1.60-1.50 (comp, 2H), 1.23 (br, 3H), 1.08 (br, 3H),1.00-0.92 (comp, 1H), 0.52 (d, 2H), 0.12 (d,2H); MS (M+1) 421.3.

[0158]4-[1-Cyclopropylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl-N,N-diisopropyl-benzamide

[0159]¹HNMR (400 MHz, CDCl₃) δ 7.31 (d, 2H), 6.92 (s, 1H), 6.85 (d, 1H),6.67 (d, 1H), 2.48 (br, 2H), 2.25 (d, 4H), 1.02-0.93 (comp, 1H)0.90-0.80 (comp, 2H), 0.53 (d, 2H), 0.12 (d, 2H); MS (M+1) 449.3.

[0160]{4-[1-Cyclopropylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl}-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone

[0161]¹HNMR (400 MHz, CDCl₃) δ 7.37 (q, 4H), 6.91 (s, 1H), 6.84 (d, 1H),6.69 (d, 1H), 3.74 (s, 3H), 2.94-2.80 (comp, 4H), 2.47 (br, 1H), 2.28(br, 4H), 0.55 (d, 2H), 0.15 (br, 2H); MS (M+1) 421.3.

[0162]{4-[1-Cyclopropylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl}-piperidin-1-yl-methanone

[0163]¹HNMR (400 MHz, CDCl₃) δ 7.35 (d, 2H), 7.15 (t, 1H), 6.92 (s, 1H),6.84 (d, 1H), 6.67 (d, 1H), 3.74 (s, 3H), 3.66-3.60 (comp, 2H),3.40-3.34 (comp, 2H), 2.25 (d, 4H), 0.53 (d, 2H), 0.12 (d, 2H); MS (M+1)433.3.

[0164]{4-[1-Cyclopropylimethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl}-morpholin-4-yl-methanone

[0165]¹HNMR (400 MHz, CDCl₃) δ 7.39 (d, 2H), 7.27 (d, 2H), 6.90 (s, 1H),6.83 (d, 1H), 6.68 (d, 1H), 2.25 (d, 4H), 0.53 (d, 2H), 0.12 (d, 2H); MS(M+1) 435.3.

[0166]N,N-Diethyl4-[1-ethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-benzamide

[0167]¹HNMR (400 MHz, CDCl₃) δ 7.32 (d, 2H), 6.89 (s, 1H), 6.82 (d, 1H),6.67 (dd, 1H), 3.74 (s, 3H), 3.50 (br, 2H), 2.42 (q, 4H) 2.25-2.22(comp, 2H); MS (M+1) 395.2.

EXAMPLE 3 ALKYLATION OFN,N-DIETHYL-4-[3-(3-METHOXY-PHENYL)-PIPERIDIN-3-YL]-BENZAMIDE

[0168] To a solution ofN,N-diethyl-4-[3-(3-methoxy-phenyl)-piperidin-3-yl]-benzamide(1equivalent) in DMF (0.5M) was added potasium carbonate (K₂CO₃) (3-10equivalents) and the alkyl or heteroaryl halide (1-5 equivalents). Thereaction mixture was stirred at 60-120° C. for 3-16 hours. The mixturewas then cooled to room temperature and filtered. The filtrate wasdiluted with diethyl ether and the ether layer was washed with brine.The organic phase was dried (MgSO₄) and concentrated. Purification byflash chromatography afforded the desired amines in yields ranging from30-85%.

[0169] The following compounds were made using a procedure analogous tothat of Example 3, starting with the appropriate amide group.

[0170]N,N-Diethyl-4-[3-(3-methoxy-phenyl)-1-pyrimidin-2-yI-piperidin-3-yl]-benzamide

[0171]¹HNMR (400 MHz, CDCl₃) δ 8.35 (d, 2H), 7.33 (d, 2H), 7.23 (d, 2H),7.14 (t, 1H), 6.91 (s, 1H), 6.86 (d, 1H), 6.68 (dd, 1H), 6.49 (t, 1H),4.29 (q, 2H), 3.87-3.80 (comp, 1H), 3.76-3.69 (comp, 1H), 3.67 (s, 3H),3.49 (br, 2H), 3.21 (br, 2H), 2.51-2.47 (comp, 2H), 1.62 (br, 2H), 1.18(br, 3H), 1.06 (br, 3H); MS (M+1) 445.4.

[0172]N,N-Diethyl-4-[3-(3-methoxy-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3-yl]-benzamide

[0173]¹HNMR (400 MHz, CDCl₃) δ 8.24-8.22 (comp, 1H), 733 (d, 2H), 6.92(s, 1H), 6.86 (d, 1H), 6.69 (dd, 2H), 4.10 (q, 2H), 3.23 (br, 2H), 2.45(br, 2H); MS (M+1) 444.2.

[0174]4-[1-Benzooxazol-2-yl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0175]¹HNMR (400 MHz, CDCl₃) δ 7.41 (d, 1H), 7.04 (t, 1H), 6.90-6.86(comp, 2H), 6.71 (dd, 1H), 4.18 (br, 2H), 3.49 (br, 2H), 2.51-2.45(comp, 2H), 1.69 (br, 2H); MS (M+1) 484.4.

[0176]N,N-Diethyl-4-[1-(5-fluoro-pyrimidin-2-yl)-3-(3-methoxy-phenyl)-piperidin-3-yl]-benzamide

[0177]¹HNMR (400 MHz, CDCl₃) δ 8.23 (s, 2H), 7.15 (t, 1H), 7.90-7.84(comp, 2H), 6.69 (dd, 1H), 4.23 (q, 2H) 3.49 (br, 2H), 2.48-2.45 (comp,2H), 1.62-1.57 (comp, 2H); MS (M+1) 463.3.

[0178]4-[1-Allyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0179]¹HNMR (400 MHz, CDCl₃) δ 7.29 (d, 2H), 7.23 (d, 2H), 7.12 (t, 1H),6.86 (s, 1H), 5.99-5.89 (comp, 1H), 5.19-5.13 (comp, 2H), 3.70 (s,3H),3.48 (br, 2H), 2.98 (d, 2H), 2.44 (br, 2H), 2.24-2.19 (comp, 2H); MS(M+1) 407.3.

EXAMPLE 4 DEPROTECTION OF METHYL ARYL ETHERS

[0180] To a solution of methyl ether (1 equivalent) in CH₂Cl₂ (0.4M) at−78° C. was added a solution of boron tribromide (1-5 equivalents) inCH₂Cl₂ (1.OM) dropwise. The reaction mixture was stirred at −78° C. for1 hour was warmed to room temperature and stirred for an additional 4-6hour. The mixture was quenched with slow addition of water and wasbrought to pH 8 with a saturated water/ammonium hydroxide (NH₄0H)solution. The aqueous layer was washed with CH₂Cl₂. The organic phasewas dried (MgSO₄) and concentrated. Purification by flash chromatographyafforded the desired phenols in yields ranging from 60-95%.

[0181] Alternatively, the methyl ethers were deprotected with sodiumhydride and ethane thiol in dimethylformamide (DMF) as follows: To asuspension of sodium hydride (NaH) (10 equivalents) in DMF (0.2M) atroom temperature was added ethane thiol (10 equivalents) dropwise. Themixture was stirred for 5 minutes. To the reaction mixture was added asolution of the methyl ether (1 equivalent) in DMF (0.2M). The mixturewas heated to 120° C. for 10-16 hours. The reaction was cooled to roomtemperature and was quenched with water. The mixture was diluted withdiethyl ether and the organic layer was washed with brine. The organicphase was dried (MgSO₄) and concentrated. Purification by flashchromatography afforded the desired phenols in yields ranging from60-95%.

[0182] The following compounds were made using a procedure similar tothat of Example 4.

[0183]4-[1-Benzyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0184]¹HNMR (400 MHz, CDCl₃) δ 7.31-7.29 (comp, 4H), 7.28-7.19 (comp,5H), 7.03 (t, 1H), 6.72 (d, 1H), 6.62 (s, 1H), 6.57 (dt 1H), 3.58-3.42(comp, 4H), 3.47 (s, 2H), 3.25 (br, 2H), 2.88 (br, 1H), 2.72 (br, 1H),2.49 (br, 1H), 2.38 (br, 1H), 2.25-1.95 (comp, 2H), 1.59-1.42 (comp,2H), 1.20 (br, 3H), 1.09 (br, 3H); MS (M+1) 443.3.

[0185]N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-(3-phenyl-propyl)-piperidin-3-y]-benzamide

[0186]¹HNMR (400 MHz, CDCl₃) δ 7.31-7.14 (comp, 9H), 7.79 (d, 1H), 6.70(s, 1H), 6.57 (dd, 1H), 3.49 (br, 2H), 2.93 (br, 1H), 2.66-2.60 (comp,2H), 2.23-2.17 (comp, 2H), 1.20 (br, 3H); MS (M+1) 471.2.

[0187]4-[1-Cyclopropylmethyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0188]¹HNMR (400 MHz, CDCl₃) δ 7.32 (d, 2H), 7.02 (t, 1H), 6.80 (d, 1H),6.53 (d, 1H), 3.50 (br, 2H), 2.42 (br, 1H), 1.56-1.51 (comp; 2H),1.00-0.90 (comp, 1H), 0.51 (d, 2H); MS (M+1) 407.1.

[0189]N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-thiazol-2-ylmethyl-piperidin-3-yl]-benzamide

[0190]¹HNMR (400 MHz, CDCl₃) δ 7.68 (d, H), 7.07 (t, 1H), 6.80-6.75(comp, 2H), 6.61 (dd, 1H), 6.40 (br, 1H), 3.51 (br, 2H) 2.54 (comp, 2H),2.21 (br; 2H), 1.60-1.50 (comp, 2H); MS (M+1) 450.2.

[0191] 4-[1-Cyclohex-3-enylmethyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0192]¹HNMR (400 MHz, CDCl₃) δ 7.32 (d, 2H), 7.05 (t, 1H), 6.81 (d, 1H),6.74 (d, 1H), 6.58 (dd, 1H), 3.50 (br, 2H), 1.89-1.80 (comp, 2H),1.70-1.63 (comp; 1H), 1.54-1.42 (comp, 2H), 1.20 (br, 3H); MS (M+1)447.2.

[0193]4-[1-Butyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0194]¹HNMR (400 MHz, CDCl₃) δ 7.30 (d, 2H), 7.05 (t, 1H), 6.80 (d, 1H),6.70 (s, 1H), 6.56 (dd, 1H), 3.50 (br, 2H), 2.93 (br, 1H), 2.69 (br,1H), 2.35-2.30 (comp, 3H), 1.54-1.42 (comp, 5H), 0.91 (t, 3H); MS (M+1)409.3

[0195]N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-(1H-imidazol-2-ylmethyl)-piperidin-3-yl]-benzamide

[0196]¹HNMR (400 MHz, CDCl₃) δ 7.17-7.12 (comp, 4H), 6.87 (s, 2H), 6.65(d, 1H), 6.52 (d, 1H), 3.53 (br, 2H), 3.27-3.15 (comp, 4H), 2.60-2.50(comp, 2H), 1.46 (br, 2H); MS (M+1) 433.3

[0197]N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-propyl-piperidin-3-yl]-benzamide

[0198]¹HNMR (400 MHz, CDCl₃) δ 7.31 (d, 2H), 7.04 (t, 1H), 6.80 (d, 1H),6.71 (s, 1H), 6.56 (dd, 1H), 3.50 (br, 2H), 2.49 (br, 1H), 2.20 (br,2H), 1.62-1.50 (comp, 4H), 0.90 (t, 3H); MS (M+1)395.3

[0199]N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-(3-methyl-butyl)-piperidin-3-yl]-benzamide

[0200]¹HNMR (400 MHz, CDCl₃) δ 7.31 (d, 2H), 7.04 (t, 1H), 6.80 (d, 1H),6.69 (s, 1H), 6.55 (dd, 1H), 3.50 (br, 2H), 2.51 (br, 1H), 2.39-2.24(comp, 3H), 1.10 (br; 3H), 0.90 (d, 6H); MS (M+1) 423.3

[0201] {4-[1-Cyclopropylmethyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-phenyl}-piperidin-1-yl-methanone

[0202]¹HNMR (400 MHz, CDCl₃) δ 7.33-7.30 (comp, 2H), 7.07 (t, 1H), 6.80(d, 1H), 6.76 (s, 1H), 6.61 (dd, 1H), 3.65 (br, 2H), 3.33 (br, 2H), 2.37(d, 2H), 2.24 (br, 2H), 1.05-0.94 (comp, 1H), 0.55 (d, 2H), 0.15 (d,2H); MS (M+1) 419.3.

[0203]4-[1-Allyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0204]¹HNMR (400 MHz, CDCl₃) δ 7.28 (comp, 2H), 7.04 (t, 1H), 6.78 (d,1H), 6.68 (s, 1H), 6.56 (dd, 1H), 6.00-5.89 (comp, 1H), 5.18 (d, 1H),5.15 (s, 1H), 3.50 (br, 2H), 2.50 (br, 1H), 2.39 (br, 1H), 1.60-1.47(comp, 2H); MS (M+1) 393.2.

[0205] N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-thiophen-3-ylmethyl-piperidin-3-yl]-benzamide

[0206]¹HNMR (400 MHz, CDCl₃) δ 7.09-7.05 (comp, 2H), 7.01 (t, 1H), 6.70(d, 1H), 6.65 (s, 1H), 6.56 (dd, 1H) 3.49 (br, 4H), 2.37 (br, 1H), 2.18(br, 2H), 1.58-1.44 (comp, 2H); MS (M+1) 449.3.

[0207]4-[1-Acetyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0208]¹HNMR (400 MHz, CDCl₃) δ 7.28-7.20 (comp, 4H), 7.07 (t, 1H), 6.84(s, 1H), 6.72 (dd, 1H), 6.66 (dd, 1H) 4.18 (d, 1H), 3.85 (d, 1H), 3.21(br, 2H), 2.04 (s, 3H), 1.59-1.47 (comp, 2H); MS (M+1) 395.2.

[0209]4-[1-But-2-enyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethylbenzamide

[0210]¹HNMR (400 MHz, CDCl₃) δ 7.28 (d, 2H), 7.04 (t, 1H), 6.78 (d, 1H),6.67 (s, 1H), 6.55 (dd, 1H), 5.60-5.57(comp, 2H), 3.50 (br, 2H), 2.36(br, 1H), 2.21 (br, 2H), 1.60-1.46 (comp, 2H); MS (M+1) 407.3.

[0211]4-[1-Cyclopropylmethyl-3-(4-fluoro-3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0212]¹HNMR (400 MHz, CDCl₃) δ 7.30 (d, 2H), 6.98 (d, 1H), 6.92 (dd,1H), 6.77 (s, 1H), 3.51 (br, 2H), 2.27 (br, 2H), 1.54 (br, 2H), 0.55 (d,2H); MS (M+1) 425.5.

[0213]4-[1-Cyclopropymethyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-dimethyl-benzamide

[0214]¹HNMR (400 MHz, CDCl₃) δ 7.33 (d, 2H), 7.04 (t, 1H), 6.81 (d, 1H),6.70 (s, 1H), 6.54 (dd, 1H), 3.05 (s, 3H), 2.41 (br, H), 1.60-1.46(comp, 2H), 0.51 (dd, 2H); MS (M+1) 379.1.

[0215]N,N-Diethyl4-[3-(3-hydroxy-phenyl)-1-(3,4,4-trifluoro-but-3-enyl)-piperidin-3-yl]-benzamide

[0216]¹HNMR (400 MHz, CDCl₃) δ 7.31-7.29 (comp, 4H), 7.28-7.19 (comp,5H), 7.03 (t, 1H), 6.72 (d, 1H), 6.62 (s, 1H), 6.57 (dt 1H), 3.50 (comp,2H), 3.47 (s, 2H), 3.25 (br, 2H), 2.88 (br, 1H), 2.72 (br; 1H), 2.49(br, 1H), 2.38 (br, 1H), 2.20 (comp, 2H), 1.51 (comp, 2H), 1.20 (br,3H), 1.09 (br, 3H); MS (M+1) 443.3.

[0217] 4-[1-Cyclopropylmethyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N-ethyl-N-methyl-benzamide

[0218]¹HNMR (400 MHz, CDCl₃) δ 7.33 (d, 2H), 7.05 (t, 1H), 6.82 (d, 1H),6.72 (s, 1H), 6.56 (d, 1H), 2.42 (br, 1H), 2.32-1.17 (comp, 4H),1.62-1.48 (comp, 2H), 0.53 (dd, 2H); MS (M+1) 393.1.

[0219]N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-(2-oxo-butyl)-piperidin-3-yl]-benzamide

[0220]¹HNMR (400 MHz, CDCl₃) δ 7.33-7.26 (comp, 1H), 7.05 (t, 1H), 6.73(d, 1H), 3.50 (br, 2H), 3.15-3.05 (comp, 1H), 2.24 (br, 1H), 2.11 (d,4H); MS (M+1) 423.1.

[0221]4-[1-Benzyl-3-(3-fluoro-5-hydroxy-phenyl)-piperidin-3-yi]-N,N-diethyl-benzamide

[0222]¹HNMR (400 MHz, CDCl₃) δ 6.49 (d, 1H), 6.38 (s, 1H), 6.29 (dt 1H),3.49 (comp, 2H), 3.45 (comp, 2H), 3.25 (br, 2H); MS (M+1) 461.3.

[0223]4-[1-Cyclopropylmethyl-3-(3-fluoro-5-hydroxy-phenyl)-piperidin-3yl]-N,N-diethyl-benzamide

[0224]¹HNMR (400 MHz, CDCl₃) δ 7.29-7.27 (comp, 2H), 7.23-7.20 (comp,2H), 6.59 (d, 1H), 6.45 (s, 1H), 6.23 (dt, 1H), 3.50 (br, 2H), 3.26 (br,2H), 2.24 (d, 2H), 2.15 (br, 2H), 0.52 (comp, 2H), 0.10 (comp, 2H), 2.40(br, 1H), 2.24 (comp, 2H), 1.53 (comp, 2H), 1.20 (br, 3H), 1.10 (br,3H); MS (M+1) 425.3.

[0225]N,N-Diethyl-4-[3-(3-fluoro-5-hydroxy-phenyl)-1-propyl-piperidin-3-yl]-benzamide

[0226]¹HNMR (400 MHz, CDCl₃) δ 6.57 (d, 1H), 6.43 (s, 1H), 6.25 (dt,1H), 3.50 (br, 2H), 3.25 (br, 2H), 2.41 (br, 2H), 2.27 (t, 2H) 2.13 (br,2H); MS (M+1) 413.3.

[0227]N,N-Diethyl-4-[1-(5-fluoro-pyrimidin-2-yl)-3-(3-hydroxy-phenyl)-piperidin-3-yl]-benzamide

[0228]¹HNMR (400 MHz, CDCl₃) δ 8.22 (s, 2H), 7.30-7.27 (comp, 2H), 7.05(t, 1H), 6.83 (d, 1H), 6.74 (t, 1H), 4.21 (q, 2H), 3.82-3.75 (comp, 1H),3.65-3.59 (comp, 2H), 3.49 (br, 2H), 2.41 (comp, 2H); MS (M+1) 449.3.

[0229]N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-pyrimidin-2-yl-piperidin-3-yl]-benzamide

[0230]¹HNMR (400 MHz, CDCl₃) δ 8.34 (s, 2H), 7.05 (comp, 1H), 6.81 (d,2H), 6.55 (d, 2H), 3.82 (comp, 1H), 3.72 (comp, 1H), 2.43 (br, 2H); MS(M+1) 431.3.

[0231]{4-[1-Cyclopropylmethyl-3-(3-hydroxy-phenyl)-piperidin-3-ylphenyl]-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone

[0232]¹HNMR (400 MHz, CDCl₃) δ 7.28 (d, 2H), 7.05 (t, 1H), 6.75 (d, 1H),6.72 (s, 1H), 6.59 (dd, 1H), 6.07 (br, 1H), 3.50 (br, 2H), 3.13 (d, 1H),2.79-2.63 (comp, 1H), 2.18 (br, 2H), 1.21 (br,3H); MS (M+1) 435.3.

[0233]N,N-Diethyl-4-[3-(3-hydroxy-phenyl)-1-(2,2,2-trifluoro-ethyl)-piperidin-3-yl]-benzamide

[0234]¹HNMR (400 MHz, CDCl₃) δ 7.38 (d, 2H), 7.27-7.19 (comp, 4H), 7.17(t, 1H), 6.74 (s, 1H), 6.60 (dd, 1H), 2.38-2.20 (comp, 4H), 1.57 (br,2H), 0.54 (d, 2H); MS (M+1) 435.3.

EXAMPLE 54-[1-BENZYL-3-(3-CARBOXYAMINO-PHENYL)-PIPERIDIN-3-YL]-N,N-DIETHYL-BENZAMIDE

[0235] A. Trifluoro-methanesulfonic acid3-[1-benzyl-3-(4-diethylcarbamoyl-phenyl)-piperidin-3-yl]-phenyl ester

[0236] To a solution of4-[1-benzyl-3-(3-hydroxy-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide(0.92 g, 2.08 mmol) in CH₂Cl₂ (15 ml) at 0° C. was added pyridine(0.25mL, 3.12 mmol) followed by dropwise addition of triflic anhydride(0.52 mL, 3.61mmol) over 5 minutes. The reaction mixture was stirred at0° C. for 1 hour and at room temperature for 2 hours. The solution wasthen cooled to 0° C. and 15 mL of cold saturated aqueous NaHCO₃ wereadded. The organic layer was separated and the aqueous layer was washedwith CH₂Cl₂ (3×20 mL). The combined organic layers were dried (MgSO₄)and concentrated. The crude residue was purified by flash chromatographywith hexanes/EtOAc (4:1) to afford 0.50 g of trifluoro-methanesulfonicacid 3-[1-benzyl-3-(4-diethylcarbamoyl-phenyl)-piperidin-3-yl]-phenylester. ¹HNMR (400 MHz, CDCl₃) δ 7.39-7.18 (comp, 12H), 7.04-6.99 (m,1H), 3.60-3.39 (comp, 4H), 3.35-3.28 (comp, 2H), 3.06-2.87 (m, 1H),2.68-2.44 (comp, 2H), 2.38-2.25 (m, 1), 2.23-1.96 (comp, 2H), 1.64-1.39(comp, 2H), 1.25-1.11 (comp, 3H), 1.10-0.99 (comp, 3H); MS (M+1) 575.2.

[0237] B.4-[1-Benzyl-3-(3-cyano-phenyl)-piperldin-3-yl]-N,N-diethyl-benzamide

[0238] To a solution of trifluoro-methanesulfonic acid3-[1-benzyl-3-(4-diethylcarbamoyl-phenyl)-piperidin-3-yl]-phenyl ester(0.40 g, 0.69 mmol) in DMF (8 mL) was added zinc cyanide (0.057 g, 0.49mmol) and tetrakis triphenylphosphine palladium (0.16 g, 0.14 mmol). Thereaction was stirred under a nitrogen atmosphere at 90° C. for 5 hours.The mixture was cooled to room temperatures and it was diluted withdiethyl ether (30 mL). The organic layer was washed with brine (5x 10mL), dried (MgSO₄) and concentrated. Purification with hexanes/EtOAc(1:1) afforded 0.28 g of4-[1-benzyl-3-(3-cyano-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide.¹HNMR (400 MHz, CDCl₃) δ 7.66 (s, 1H), 7.69-7.20 (comp, 10H), 7.15-7.13(comp, 2H) 3.60-3.38 (comp, 4H), 3.31-3.19 (comp, 2H), 3.09-2.94 (m,1H), 2.58-2.45 (comp, 2H), 2.22-2.17 (comp, 3H), 1.71-1.61 (m, 1H),1.28-1.16 (comp, 3H), 1.17-1.08 (comp, 3H); MS (M+1) 452.2.

[0239] C.4-[1-Benzyl-3-(3-carboxyamino-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0240] To a solution of4-[1-benzyl-cyano-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide (0.50 g,1.11 mmol) in ethanol (5 mL) was added 3N aqueous Na₂CO₃ (3.25 mL) and30% aqueous H₂O₂ (0.88 mL). The reaction mixture was stirred at roomtemperature for 8 hours. The mixture was diluted with water (2 mL) andthe aqueous layer was washed with CH₂Cl₂ (3×10 mL). The organic layerwas dried (MgSO₄) and concentrated. The residue was purified by flashchromatography with CH₂Cl₂/methanol (MeOH) (10:1) to afford 0.42 mg of¹HNMR (400 MHz, CDCl₃) δ 7.80 (s, 1H), 7.56 (d, 1H), 7.40-7.16 (comp,11H), 5.99 (br, 1H), 5.59 (br, 1H), 3.59-3.39 (comp, 4H), 3.34-3.18(comp, 2H), 3.06-2.88 (m, 1H), 2.81-2.62 (m, 1H), 2.41-2.27 (m, 1H),2.25-2.17 (comp, 3H), 2.58-2.41 (comp, 2H), 1.28-1.18 (comp, 3H),1.17-1.00 (comp, 3H) MS (M+1) 470.3.

[0241] The following examples were prepared by methods similar to thosedescribed above in Example 5.

[0242]4-[1-(2,2,2-trifluoroethyl)-3-(3-carboxyamino-phenyl)-piperidin-3-yl]-N,N-diethyl-benzamide

[0243]¹HNMR (400 MHz, CDCl₃) δ 7.93 (s, 1H), 7.64-7.61 (m, 1H), 6.24(br, 1H), 3.56-3.42 (comp, 2H), 2.62 (t, 1H), 1.18-1.10 (comp, 3H); MS(M+1) 462.3.

[0244]N,N-Diethyl-4-[3-(3-carboxyamino-phenyl)-1-thiazol-2-ylmethyl-piperidin-3-yl]-benzamide

[0245]¹HNMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.72 (d, 1H), 7.68-7.65 (m,1H), 5.93 (br, 1H), 2.77-2.67 (comp, 2H), 1.08 (comp, 3H); MS (M+1)477.3.

[0246]N,N-Diethyl-4-[1-furan-2-ylmethyl-3-(3-carboxyamino-phenyl)-piperidin-3-yl]-benzamide

[0247]¹HNMR (400 MHz, CDCl₃) δ 7.92 (s, 1H), 7.61 (d, 1H), 6.23 (br,1H), 3.27-3.21 (comp, 2H), 1.18-1.01 (comp, 3H); MS (M+1) 460.3.

EXAMPLE 61-CYCLOPROPYLMETHYL-3-(3-METHOXY-PHENYL)-3-(4-THIOPHEN-2-YL-PHENYL)-PIPERIDINE

[0248] To a solution of trifluoro-methanesulfonic acid4-[1-cyclopropylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl ester(0.1 g, 0.2 mmol) in ethanol (4.5 mL) and water (0.5 mL) was added2-thiophene boronic acid (0.052 g, 0.5 mmol) and sodium carbonate (0.037g, 0.29 mmol) and tetrakis tripheny;phosphine palladium (0.02 g, 0.18mmol). The reaction mixture was heated to reflux for 2 hours. Themixture was then filtered and the filtrate was concentrated undervacuum. The residue was purified by flash chromatography withhexanes/EtOAc (3:1) to afford 0.08 g of1-cyclopropylmethyl-3-(3-methoxy-phenyl)-3-(4-thiophen-2-yl-phenyl)-piperidine.¹HNMR (400 MHz, CDCl₃) δ 749 (d, 2H), 7.35 (d, 2H), 7.22-7.06 (comp,3H), 7.05-7.00 (m, 1H), 6.96 (s, 1H), 6.89 (d, 1H), 6.70-6.67 (m, 1H),3.76 (s, 3H), 3.17-2.82 (comp, 2H), 2.61-2.39 (comp, 2H), 2.27-2.18(comp, 4H), 1.62-1.39 (comp, 3H), 0.60-0.45 (comp, 2H), 0.18-0.11 (comp,2H); MS (M+1) 404.2.

EXAMPLE 73-{4-[1-ALLYL-3-(3-METHOXY-PHENYL)-PIPERIDIN-3-YL]-PHENYL}-PENTAN-3-OL

[0249] To a solution of4-[1-allylmethyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-benzoic acidmethyl ester (1.71 g, 4.68 mmol) in THF (30 mL) at 0° C. was addedethylmagnesium bromide (1M in tert-butylmethylether, 46.8 mL, 46.8mmol). The ice bath was removed and the reaction was stirred at roomtemperature for 1 hour. The mixture was quenched with slow addition ofwater (15 mL). The aqueous layer was washed with diethyl ether (3×30mL). The combined extracts were dried (MgSO₄) and concentrated to afford1.67 g (91%) of3-{4-[1-allyl-3-(3-methoxy-phenyl)-piperidin-3-yl]-phenyl}-pentan-3-ol.¹HNMR (400 MHz, CDCl₃) δ 7.23-7.20 (comp, 5H), 7.15 (t, 1H), 6.85 6.84(comp, 2H), 6.66 (dd, 1H), 6.01-5.92 (m, 1H), 5.20 (s, 1H), 5.17-5.14(m, 1H), 3.71 (s, 3H), 3.04-2.95 (comp, 2H), 2.88-2.72 (comp, 2H),2.50-2.40 (cornp, 2H), 2.27-2.21 (comp, 2H), 1.83-1.71 (comp, 4H),1.57-1.49 (comp, 2H), 0.71 (dt, 6H); MS (M+1) 394.3.

[0250] The following compounds were prepared by a procedure analogous tothat of Example 4 for the deprotection of methyl ethers.

[0251]3-{1-Allyl-3-[4-(1-ethyl-1-hydroxy-propyl)-phenyl]-piperidin-3-yl}-phenol

[0252]¹HNMR (400 MHz, CDCl₃) δ 7.21 (s, 5H), 7.09 (t, 1H), 6.84 (d, 1H),6.73 (s, 1H), 6.55 (dd, 1H), 6.02-5.92 (m, 1H), 5.20-5.14 (comp, 2H),3.07-2.96 (comp, 2H), 2.88-2.82 (comp, 2H), 2.50-2.40 (comp, 2H),2.25-2.20 (comp, 2H), 1.82-1.72 (comp, 4H), 1.65 (br, 1H), 1.61-1.52(comp, 2H), 0.71 (t, 6H); MS (M+1) 380.3.

[0253]3-[3-[4-(1-Ethyl-1-hydroxy-propyl)-phenyl]-1-(2,2,2-trifluoro-ethyl)-piperidin-3-yl]-phenol

[0254]¹HNMR (400 MHz, CDCl₃) δ 6.84 (dd, 1H), 6.79 (t, 1H), 4.97 (br,1H), 2.23-2.20 (comp, 2H), 0.72 (t, 6H); MS (M+1) 422.2.

[0255]3-{3-[4-(1-Ethyl-1-hydroxy-propyl)-phenyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3-yl}-phenol

[0256]¹HNMR (400 MHz, CDCl₃) δ 8.17-8.16 (m, 1H), 7.07 (t, 1H), 6.71 (d,1H), 4.25 (d, 1H), 3.96 (d, 1H), 2.47-2.35 (comp, 2H); MS (M+1) 417.3.

[0257]3-{1-Cyclopropylmethyl-3-[4-(1-ethyl-1-hydroxy-propyl)-phenyl]-piperidin-3-yl}-phenol

[0258]¹HNMR (400 MHz, CDCl₃) δ 7.10 (t, 1H), 6.80 (d, 1H), 6.64 (d, 1H),2.32 (br, 1H), 2.24 (br, 1H), 0.58 (d, 2H); MS (M+1) 394.4.

[0259] The following compounds were made using the procedure of Example7 followed by conversion of R³=OH to R³=CONH₂ according to the procedureof Example 5.

[0260]3-{1-Allyl-3-[4-(1-ethyl-1-hydroxy-propyl)-phenyl]-piperidin-3-yl}-benzamide

[0261]¹HNMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.54 (d, 1H), 7.40 (d, 1H),7.30 (t, 1H), 7.24-7.15 (comp, 4H), 6.06-5.94 (comp, 2H), 5.56 (br, 1H),5.21-5.16 (comp, 2H), 3.00 (d, 2H), 2.69 (br, 1H), 2.56 (br, 1H),2.42-2.28 (comp, 2H), 2.27-2.20 (m, 1H), 1.82-1.70 (comp, 4H), 1.64 (br,1H), 1.60-1.42 (comp, 2H), 0.71 (dt, 6H); MS (M+1) 407.3.

[0262]3-{3-[4-(1-Ethyl-1-hydroxy-propyl)-phenyl]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3-yl}-benzamide

[0263]¹HNMR (400 MHz, CDCl₃) δ 8.22 (d, 1H), 8.11 (s, 1H), 7.31 (t, 1H),2.63-2.57 (comp, 2H), 2.52-2.39 (comp, 2H), 0.69 (t, 6H); MS (M+1)444.3.

[0264]3-[3-[4-(1-Ethyl-1-hydroxy-propyl)-phenyl]-1-(2,2,2-trifluoro-ethyl)-piperidin-3-yl]-benzamide

[0265]¹HNMR (400 MHz, CDCl₃) δ 7.95 (s, 1H), 7.23 (d, 2H), 7.15 (d, 2H),5.62 (br, 1H), 2.86 (d, 2H), 2.60-2.54 (m, 1H), 0.71 (t, 6H); MS (M+1)431.3.

EXAMPLE 8 PROPIONIC ACID3-(1-CYCLOPROPYLMETHYL-3-P-TOLYL-PIPERIDIN-3-YL)-PHENYL ESTER

[0266] To a solution of3-(1-cyclopropylmethyl-3-p-tolyl-piperidin-3-yl)-phenol (65 mg, 0.15mmol) in CH₂Cl₂ (2 ml) at room temperature were added DMAP (18 mg, 0.15mmol), triethylamine (0.071 mL, 0.52 mmol) and propionyl chloride (0.038mL, 0.45 mmol). The reaction mixture was stirred at room temperature for12 hours. The reaction was partitioned between 5 mL CH₂Cl₂ and 5 mL ofaqueous saturated NaHCO₃. The aqueous layer was washed with CH₂Cl₂ (3×5mL), dried over Na₂SO₄ and concentrated. Purification by flashchromatography with hexanes/EtOAc (1:1) afforded 58 mg of propionic acid3-(1-cyclopropylmethyl-3-p-tolyl-piperidin-3-yl)-phenyl ester. ¹HNMR(400 MHz, CDCl₃) δ 7.33 (d, 2H), 7.26-7.19 (comp, 3H), 7.16-7.03 (comp,2H), 6.89-6.86 (m, 1H), 3.59-3.43 (comp, 2H), 3.35-3.19 (comp, 2H),2.59-2.53 (q, 2H), 2.52-2.41 (comp, 2H), 2.27-2.18 (comp, 4H), 1.57-1.44(comp, 2H), 1.31-1.19 (t, 3H), 1.18-1.09 (comp, 3H), 1.08-1.01 (comp,3H), 1.00-0.91 (m, 1H), 0.59-0.49 (comp, 2H), 0.19-0.11 (comp,1H); MS(M+1) 463.3.

[0267] The following compound was made using a procedure similar to thatof Example 8.

[0268] Isobutyric Acid3-[1-cyclopropylmethyl-3-(4-diethylcarbamoyl-phenyl)-piperidin-3-yl]-phenylester

[0269]¹HNMR (400 MHz, CDCl₃) δ 7.36-7.29 (comp, 2H) 7.10-7.02 (comp,2H), 6.89-6.85 (m, 1H), 3.01-2.82 (comp, 2H), 2.81-2.75 (m, 1H), 1.28(d, 3H); MS (M+1) 477.3.

EXAMPLE 94-r4-CYCLOPROPYLMETHYL-2-(3-HYDROXY-PHENYL)-MORPHOLIN-2-YL1-N,N-DIETHYLBENZAMIDE

[0270] A. (4-Bromo-phenyl)-(3-methoxy-phenyl)-methanol

[0271] To a suspension of magnesium (2.4 g, 100 mmmol), in THF (20 mL)at room temperature was added dropwise a solution of bromoanisole (9.1mL, 71.4 mmol) in THF (30 mL). The reaction mixture was stirred at roomtemperature for 2 h and at 60° C. for 2 h. The mixture was cooled toroom temperature and a solution of 4-bromobenzaldehyde (13.2 g, 71.4mmol) was added over 5 min. The reaction mixture was stirred at roomtemperature for 3 h and was quenched by addition of aqueous saturatedammonium chloride (NH₄Cl) (30 mL). The aqueous layer was washed withether (3×40 mL), dried over Na₂SO₄ and concentrated. Purification byflash chromatography with hexanes/EtOAc (10:1) afforded 16.95 g of(4-bromo-phenyl)-(3-methoxy-phenyl)-methanol. ¹HNMR (400 MHz, CDCl₃) δ7.46-7.41 (comp, 2H), 7.27-7.18 (comp, 3H), 6.91-6.87 (comp, 2H),6.81-6.78 (m, 1H), 5.73 (s, 1H), 3.76 (s, 3H); MS (M+1) 294.2.

[0272] B. (4-Bromo-phenyl)-(3-methoxy-phenyl)-methanone

[0273] To a solution of DMSO (8.13 mL, 114.7 mmol) in CH₂Cl₂ (80 mL) at−78 was added solution of trifluoroacetic acid (TFAA) (12.12 mL, 86.0mmol) in CH₂Cl₂ (50 mL) over 5 min. The mixture was stirred for 20 minand a solution of (4-bromo-phenyl)-(3-methoxy-phenyl)-methanol (16.8 g,57.4 mmol) in CH₂Cl₂ (50 mL) was added dropwise over 5 min. The reactionmixture was stirred at −78° C. for 30 min and Et3N (24.0 mL, 172 mmo)was added. The mixture was stirred at −78° C. for an additional 30 minand at room temperature for 1 h. The CH₂Cl₂ layer was washed with brine(3×30 mL), dried over Na₂SO₄ and concentrated. Purification withhexanes/EtOAc (10:1) afforded 16.0 g of(4-Bromo-phenyl)-(3-methoxy-phenyl)-methanone. ¹HNMR (400 MHz, CDCl₃) δ7.67-7.66 (comp, 2H), 7.64-7.60 (comp, 2H), 7.37 (m, 1H), 7.34-7.27(comp, 2H), 7.14-7.11 (m, 1H), 3.84 (s, 3H).

[0274] C. 2-Amino-1-(4-bromo-phenyl)-1-(3-methoxy-phenyl)-ethanol

[0275] To a solution of (4-bromo-phenyl)-(3-methoxy-phenyl)-methanone(2.06 g, 7.07 mmol), in CH₂Cl₂ (3.5 mL) at room temperature was addedZnl₂ (0.15 g, 0.47 mmol) followed by addition of TMSCN (4.29 mL, 32.2mmol). The reaction mixture was stirred at room temperature for 3 h andwas quenched by addition of brine (20 mL). The aqueous layer was washedwith CH₂Cl₂ (3×30 mL) and the combined organic extracts were dried overNa₂SO₄ and concentrated to afford an oil. The resulting oil wasdissolved in THF (7 mL) and the solution was added dropwise to asolution of lithium aluminum hydride (LAH) in THF (1M, 8.13 mL) at 0° C.The mixture was stirred at 0° C. for 1 h and at room temperature for 1h. To the solution was added H₂O (1.5 mL) followed by addition of 15%aqueous sodium hydroxide (NaOH) (1.5 mL) and H₂O (4.5 mL). The mixturewas filtered trough celite and the celite was washed with EtOAc (20 mL).The filtrate was dried over MgSO₄ vand concentrated. Purification byflash chromatography with CH₂Cl₂/MeOH (20:1) afforded 2.1 g of2-amino-1-(4-bromo-phenyl)-1-(3-methoxy-phenyl)-ethanol. ¹HNMR (400 MHz,CDCl₃) δ 7.44-7.40 (comp, 2H), 7.33-7.26 (comp, 2H), 7.24-7.20 (m, 1H),7.01-6.99 (m, 1H), 6.97-6.94 (m, 1H), 3.77 (s, 3H), 3.47-3-35 (comp,2H), 3.29-3.24 (comp, 2H); MS (M+1) 304.1, 306.1.

[0276] D.N-[2-(4-Bromo-phenyl)-2-hydroxy-2-(3-methoxy-phenyl)-ethyl]-2-chloro-acetamide

[0277] To a solution of2-amino-1-(4-bromo-phenyl)-1-(3-methoxy-phenyl)-ethanol (0.94 g, 2.92mmol) in toluene (10 mL) at 0° C. was added triethylamine (0.41 mL, 3.07mmol). To the reaction mixture was added a solution ofchloroacetylchloride (0.23 mL, 2.92 mmol) in toluene (1 mL) and thereaction was stirred at 0° C. for 30 min. and at room temperature for 1h. To the reaction was added cold water (10 mL) and the mixture wasstirred for 10 min. EtOAc was added (20 mL) and the layers wereseparated. The aqueous layer was washed with EtOAc (2×20 mL) and thecombined organic extracts were dried over MgSO₄, and concentrated.Purification by flash chromatography with hexanes/EtOAc (4:1) afforded1.08 g ofN-[2-(4-bromo-phenyl)-2-hydroxy-2-(3-methoxy-phenyl)-ethyl]-2-chloro-acetamide.¹HNMR (400 MHz, CDCl₃) δ 7.45-7.41 (comp, 2H), 7.29-7.20 (comp, 3H),6.97-6.96 (m, 1H), 6.93-6.90 (m, 1H), 6.86-6.85 (m, 1H), 6.85-6.79 (m,1H), 4.14-3.98 (comp, 2H), 3.95 (s, 2H), 3.77 (s, 3H); MS (M+1) 380.0,382.0.

[0278] E. 6-(4-Bromo-phenyl)-6-(3-methoxy-phenyl)-morpholin-3-one

[0279] To a solution ofN-[2-(4-bromo-phenyl)-2-hydroxy-2-(3-methoxy-phenyl)-ethyl]-2-chloro-acetamide(3.67 g, 9.2 mmol), in benzene (205 mL) at room temperature was addedt-BuOK (4.54 g, 40.5 mmol). The reaction mixture was stirred at roomtemperature for 2 h. To the mixture was added water (40 mL) and theaqueous layer was washed with CH₂Cl₂ (2×50 mL). The combined organicextracts were dried over MgSO₄ and concentrated. Purification by flashchromatography with hexanes/EtOAc (3:1) afforded 3.34 g of6-(4-bromo-phenyl)-6-(3-methoxy-phenyl)-morpholin-3-one. ¹HNMR (400 MHz,CDCl₃) δ 7.46-7.41 (comp, 2H), 7.27-7.17 (comp, 2H), 6.89-6.70 (comp,3H), 6.69 (br, 1H), 4.10 (s, 2H), 3.93-3.80 (comp, 2H), 3.76 (s, 3H); MS(M+1) 362.1, 364.1.

[0280] F. 2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-morpholine

[0281] To a solution of LAH in THF (1M, 13.9 mL) at 0° C. was added asolution of 6-(4-bromo-phenyl)-6-(3-methoxy-phenyl)-morpholin-3-one(3.34 g, 9.23 mmol) in THF (15 mL). The reaction mixture was stirred at0° C. for 1 h and at room temperature for 16 h. To the mixture was addedH₂O (6.2 mL) followed by addition of 15% aqueous NaOH (6.2 mL) and H₂O(7 mL). The mixture was filtered through celite and the celite waswashed with EtOAc (50 mL). The filtrate was dried over MgSO₄ andconcentrated to afford 2.82 g of2-(4-bromo-phenyl)-2-(3-methoxy-phenyl)-morpholine. ¹HNMR (400 MHz,CDCl₃) δ 7.43-7.36 (comp, 2H), 7.33-7.20 (comp, 3H), 6.98-6.82 (comp,2H), 6.79-6.75 (m, 1H), 3.76 (s, 3H), 3.68-3.69 (comp, 2H), 3.45-3.29(comp, 2H), 2.93-2.88 (comp, 2H); MS (M+1) 348.01, 350.0.

[0282] G.2-(4-Bromo-phenyl)4-cyclopropylmethyl-2-(3-methoxy-phenyl)-morpholine

[0283] Prepared by methods similar to those described in Examples 2 and3. ¹HNMR (400 MHz, CDCl₃) δ 7.42-7.38 (comp, 2H), 7.30-7.18 (comp, 3H),7.08-6.97 (m, 1H), 6.96-6.84 (m, 1H), 6.79-6.71 (m, 1H), 3.76 (s, 3H),3.75-3.61 (comp, 2H), 3.15-2.88 (comp, 2H), 2,59-2.51 (comp, 2H),2.29-2.19 (comp, 2H), 1.01-0.84 (m, 1H), 0.50-0.49 (comp, 2H), 0.18-0.11(comp, 2H); MS (M+1) 402.0, 404.0.

[0284] H.4-[4-Cyclopropylmethyl-2-(3-methoxy-phenyl)-morpholin-2-yl]-benzoic acidmethyl ester

[0285] Prepared by a procedure similar to that described in example 1D.¹HNMR (400 MHz, CDCl₃) δ 7.94 (d, 2H), 7.48 (d, 2H), 7.21-7.18 (m, 1H),6.98 (s, 1H), 6.91 (d, 1H), 6.74 (dd, 1H), 3.87 (s, 3H), 3.75 (s, 3H),3.74-3.63 (comp, 2H), 3.09-2.92 (comp, 2H), 2.56-2.48 (comp, 2H),2.31-2.18 (comp, 2H), 0.98-0.88 (m, IH), 0.59-0.51 (comp, 2H), 0.14-0.10(comp, 1H); MS (M+1) 382.1.

[0286] I.4-[4-Cyclopropylmethyl-2-(3-methoxy-phenyl)-morpholin-2-yl]-N,N-diethyl-benzamide

[0287] Prepared by a method similar to that described in Example 1E.¹HNMR (400 MHz, CDCl₃) δ 7.40 (d, 1H), 7.28 (d, 2H), 7.23-7.18 (m, 1H),7.06-6.98 (m, 1H), 6.93 (d, 1H) 6.75 (dd, 1H), 3.76 (s, 3H), 3.75-3.76(comp, 2H), 3.55-3.49 (comp, 2H), 3.32-3.19 (comp, 2H), 3.16-3.02 (m,1H), 2.99-2.84 (m, 1H), 2.58-2.43 (comp, 2H), 2.34-2.26 (m, 1H),2.25-2.18 (m, 1H), 1.26-1.17 (comp, 3H), 1.16-1.04 (comp, 3H), 0.99-0.90(m, 1H), 0.59-0.51 (comp, 2H), 0.14-0.10 (comp, 2H); MS (M+1) 423.3.

[0288] J.4-[4-Cyclopropylmethyl-2-(3-hydroxy-phenyl)-morpholin-2-yl]-N,N-diethyl-benzamide

[0289] Prepared by a method similar to that described- in Example 4.¹HNMR (400 MHz, CDCl₃) δ 7.38 (d, 1H), 7.26 (d, 2H), 7.12-7.06 (m, 1H),6.91 (d, 1H), 6.82 (s, 1H), 6.61 (dd, 1H), 3.79-3.63 (comp, 2H),3.59-3.42 (comp, 2H), 3.35-3.19 (comp, 2H), 3.08-2.83 (comp, 2H),2.61-2.44 (comp, 2H), 2.32-2.18 (comp, 2H), 1.29-1.19 (comp, 3H),1.18-1.01 (comp, 3H), 0.99-0.89 (m, 1H), 0.59-0.49 (comp, 2H), 0.15-0.10(comp, 2H); MS (M+1) 409.1.

[0290] The following examples were prepared by procedures describedabove in Example 9.

[0291]4-[4-Allyl-2-(3-hydroxy-phenyl)-morpholin-2-yl]-N,N-diethyl-benzamide

[0292]¹HNMR (400 MHz, CDCl₃) δ 6.81 (s, 1H), 6.02-5.83 (m, 1H),5.29-5.16 (comp, 2H), 3.04-2.98 (comp, 2H), 2.58-2.43 (comp, 2H); MS(M+1) 395.3.

[0293]4-[4-Benzyl-2-(3-hydroxy-phenyl)-morpholin-2-yl]-N,N-diethyl-benzamide

[0294]¹HNMR (400 MHz, CDCl₃) δ 7.13-7.06 (m, 1H), 6.81-6.75 (comp, 2H),6.67 (d, 1H), 3.79-3.61 (comp, 2H), 3.32-3.18 (comp, 2H); MS (M+1)445.3.

[0295] The following compound was prepared by the procedure of Example 9and subsequent conversion of R³=OH to R³=CONH₂ according to theprocedure of Example 5.

[0296]4-14-Cyclopropylmethyl-2-(3-carboxyamino-phenyl)-morpholin-2-yl]-N,N-diethyl-benzamide

[0297]¹HNMR.(400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.70-7.61 (comp, 1H),3.81-3.63 (comp, 2H), 0.61-0.44 (comp, 2H), 0.21-0.15 (comp, 2H); MS(M+1) 436.3.

EXAMPLE 10

[0298] A. (5-Bromo-pyridin-2-yl)-(3-methoxy-phenyl)-acetonitrile

[0299] To a suspension of hexane washed 60% sodium hydride (2.65, 66.0mmol) in DMF (30 mL) at 0° C. was added 3-methoxyphenyl acetonitrile(8.0 g, 54.3 mmol). The reaction mixture was stirred at 0° C. for 30min. A solution of 2,5-dibromopyridine (15.45 g, 65.2 mmol) in DMF (20mL) was added and the reaction was stirred at room temperature for 20min and at 50° C. for 30 min. To the reaction mixture was added H₂O (20mL) and Et₂O (200 mL). The organic layer was washed with brine (5×50mL), dried over Na₂SO₄ and concentrated. Purification by flashchromatography with hexanes/EtOAc (10:1) afforded 10.6 g of(5-Bromo-pyridin-2-yl)-(3-methoxy-phenyl)-acetonitrile. ¹HNMR (400 MHz,CDCl₃) δ 8.63 (s,1H), 7.80 (dd, 1H), 7.27 (comp, 2H), 6.98 (d, 1H), 6.87(s,1H), 6.84 (m, 1H), 5.28 (s, 1H), 5.23 (s, 3H); MS (M+1) 303.0, 305.0.

[0300] B.2-(5-Bromo-pyridin-2-yl)-5-chloro-2-(3-methoxy-phenyl)-pentanenitrile

[0301] To a suspension of hexane washed 60% sodium hydride (0.35 g, 8.6mmol) in DMF (2 mL) at 0° C. was added a solution of(5-bromo-pyridin-2-yl)-(3-methoxy-phenyl)-acetonitrile (1.75 g, 5.76mmol) in DMF (5 mL). The reaction mixture was stirred at 0° C. for 30min and at room temperature for 1 h. 1-bromo-3-chloropropane (0.69 mL,6.91 mmol) was added and the mixture was stirred at room temperature for4 h. To the reaction mixture was added H₂O (5 mL) and Et₂O and theorganic layer was washed with brine (5×5 mL), dried over Na₂SO₄ andconcentrated. Purification by flash chromatography with hexanes/EtOAc(10:1) yielded 1.81 g of2-(5-bromo-pyridin-2-yl)-5-chloro-2-(3-methoxy-phenyl)-pentanenitrile.¹HNMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 7.76 (dd, 1H), 7.36 (d, 1h),7.27-7.21 (m, 1H), 7.03 (d, 1H), 6.98 (s, 1H), 6.82 (dd,1H), 4.77 (s,3H), 3.55 (t, 2H), 2.79-2.70 (comp, 1H), 2.62-2.52 (comp, 1H) 1.89-1.79(comp, 2H); MS (M+1)378.8, 380.8.

[0302] C.5-Bromo-3′-(3-methoxy-phenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl

[0303] To a solution of2-(5-bromo-pyridin-2-yl)-5-chloro-2-(3-methoxy-phenyl)-pentanenitrile(0.54 g, 1.43 mmol) in CH₂Cl₂ (3 mL) at −78° C. was added DIBAL inCH₂Cl₂ (1M, 3.2 mL). The reaction mixture was stirred at −78 for 1 h andat room temperature for 4 h. The solution was poured to a saturatedaqueous solution of Rochelle's salt (10 mL) and the resulting mixturewas stirred vigorously for 16 h. The aqueous layer was washed withCH₂Cl₂ (3×10 mL), and the combined extracts were dried over Na₂SO₄ andconcentrated. Purification by flash chromatography with CH₂Cl₂/MeOH(10:1) yielded 0.36 g of5-bromo-3′-(3-methoxy-phenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl.¹HNMR (400 MHz, CDCl₃) δ 8.62 (s, 1H), 7.63 (dd, 1H), 7.24-7.18(m, 1H),6.91 (d, 1H) 6.81-6.67 (comp, 3H), 3.96-3.90 (m, 1H), 3.75 (s, 3H),3.09-3.00 (comp, 2H), 2.82-2.74 (m, 1H), 2.54-2.48 (m, IH), 2.41-2.34(m, 1H) 1.64-1.60 (m, 1H) 1.38-1.31 (m, 1H); MS(M+1) 347.1, 349.1.

[0304] D.5-Bromo-1′-benzyl-3′-(3-methoxy-phenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl

[0305] Prepared by methods similar to those described in Examples 2 and3.

[0306]¹HNMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 7.62 (dd, 1H), 7.42-7.21(comp, 6H), 7.20-7.12 (m, 1H), 7.01 (d, 1H), 6.81-6.74 (m, 1H), 6.67(dd, 1H) 3.78 (s, 3H), 3.59-3.41 (comp, 2H), 3.20-3.12 (m, 1H),2.81-2.25 (comp, 4H), 2.18-2.04 (m, 1H), 1.62-1.41 (comp, 2H); MS(M+1)437.2, 439.3.

[0307] E.1′-Benzyl-3′-(3-methoxy-phenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-5-carboxylicacid methyl ester

[0308] Prepared by a method similar to that of Example 1D.

[0309]¹HNMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.10 (dd, IH) 7.41-7.01(comp, 7H), 6.81-6.77 (comp, 2H), 6.67 (dd, 1H), 3.90 (s, 3H), 3.70 (s,3H), 3.61-3.42 (comp, 2H), 3.25-3.15 (m, 1H), 2.85-2.75 (comp, 2H),2.61-2.53 (m, 1H), 2.41-2.38 (m, 1H), 2.20-2.12 (m, 1H), 1.62-1.55(comp, 2H); MS(M+1) 417.2.

[0310] F.1′-Benzyl-3′-(3-methoxy-phenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-5-carboxylicacid diethylamide

[0311] Prepared by a method similar to that of Example 1E.

[0312]¹HNMR (400 MHz, CDCl₃) δ 8.53 (s, 1H), 7.55 (dd, 1H), 7.38-7.21(comp, 5H), 7.18-7.09 (comp, 2H), 6.83-6.78 (comp, 2H), 6.68-6.62 (m,1H), 3.71 (s, 3H), 3.60-3.42 (comp, 4H), 3.38-3.22 (comp 2H), 3.18-3.07(m, 1H), 2.92-2.82 (m, 1H), 2.65-2.61 (m, 1H), 2.58-2.40 (comp, 2H),2.18-2.03 (m, 1H), 1.64-1.43 (comp, 2H), 1.34-1.10 (comp, 6H); MS (M+1)449.3

[0313] G.1′-Benzyl-3′-(3-hydroxy-phenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-5-carboxylicacid diethylamide

[0314] Prepared by a method similar to that of Example 4. ¹HNMR (400MHz, CDCl₃) δ 8.53 (s, 1H), 7.55 (d, 1H), 7.40-7.21 (comp, 5H),7.19-7.08 (m, 1H), 7.03-6.89 (m, 1H), 6.77-6.62 (comp, 2H), 6.58-6.52(m, 1H), 3.60-3.42 (comp, 4H), 3.36-3.22 (comp, 2H), 3.18-3.04 (m, 1H),2.82-2.78 (m 1H), 2.71-2.26 (comp, 3H), 2.18-2.03 (m, 1H), 1.62-1.44(comp, 2H), 1.35-1.10 (comp, 6H); MS(M+1) 444.2.

[0315] The following compounds were prepared by methods similar to thosedescribed in Example 10.

[0316]1′-(5-Fluoro-pyrimidin-2-yl)-3′-(3-hydroxy-phenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-5-carboxylicacid diethylamide

[0317]¹HNMR (400 MHz, CDCl₃) δ 8.20 (s, 2H), 4.57 (d, 1H), 4.17 (d, 1H);MS (M+1) 450.3.

[0318]3′-(3-Hydroxy-phenyl)-1′-pyrimidin-2-yl-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-5-carboxylicacid diethylamide

[0319]¹HNMR (400 MHz, CDCl₃) δ 8.33(s, 2H) 6.49 (d, 2H) 4.57 (d, 1H),4.17 (d, 1H); MS(M+1) 432.3.

[0320]1′-Cyclopropylmethyl-3′-(3-hydroxy-phenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-5-carboxylicacid diethylamide

[0321]¹HNMR (400 MHz, CDCl₃) δ 7.58 (dd, 1H), 1.01-0.84 (m, 1H),0.57-0.49 (comp, 2H), 0.17-0.11 (comp, 2H); MS(M+1) 408.4.

[0322]3′-(3-Hydroxy-phenyl)-1′-propyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-5-carboxylicacid diethylamide

[0323]¹HNMR (400 MHz, CDCl₃) δ 6.78 (s, 1H), 6.62 (d, 1H), 2.20-2.12 (m,1H), 1.160.99 (comp, 3H); MS(M+1) 396.4.

[0324]3′-(3-Hydroxy-phenyl)-1′-pentyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-5-carboxylicacid diethylamide

[0325]¹HNMR (400 MHz, CDCl₃) δ 2.60-2.40 (comp, 4H), 1.41-1.10 (comp,8H), 0.87 (t, 3H); MS(M+1) 424.3.

[0326]3′-(3-Hydroxy-phenyl)-1′-isobutyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-5-carboxylicacid diethylamide

[0327]¹HNMR (400 MHz, CDCl₃) δ 7.58 (dd, 1H), 6.82 (s, 1H), 3.31-3.23(comp, 2H), 1.00-0.70 (comp, 6H); MS (M+1) 410.3.

[0328]3′-(3-Hydroxy-phenyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,1′;3′,2″]terpyridine-5″-carboxylicacid diethylamide

[0329]¹HNMR (400 MHz, CDCl₃) δ 9.02 (s, 1H), 8.29 (d, 1H), 7.39-7.34 (m,1H), 6.87 (br, 1H); MS (M+1) 431.3.

[0330]3′-(3-Hydroxy-phenyl)-1′-(2-methyl-butyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl-5-carboxylicacid diethylamide

[0331]¹HNMR (400 MHz, CDCl₃) δ 8.53-8.50 (m, 1H), 6.83 (s, 1H),2.92-2.64 (comp, 2H), 1.17-1.09 (comp, 3H); MS (M+1) 424.4.

1. A compound of the formula

R¹ is hydrogen, (C₀-C₈)alkoxy-(C₁-C₈)alkyl-, wherein the total number of carbon atoms is eight or less, aryl, aryl-(C₁-C₈)alkyl-, heteroaryl, heteroaryl-(C₁-C₈)alkyl-, heterocyclic, heterocyclic-(C₁-C₈)alkyl, (C₃-C₇)cycloalkyl-, or (C₃-C₇)cycloalkyl-(C₁-C₈)alkyl, wherein said aryl and the aryl moiety of said aryl-(C₁-C₈)alkyl- are selected, independently, from phenyl and napthyl, and wherein said heteroaryl and the heteroaryl moiety of said heteroaryl-(C₁-C₈)alkyl- are selected, independently, from pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, 1,2,5-thiadiazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolyl, oxadiazoyl, isoxazoyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyridinyl, and pyrimidinyl; and wherein said heterocyclic and the heterocyclic moiety of said heterocyclic-(C₁-C₈)alkyl- are selected from saturated or unsaturated nonaromatic monocyclic or bicyclic ring systems, wherein said monocyclic ring systems contain from four to seven ring carbon atoms, from one to three of which may optionally be replaced with O, N or S, and wherein said bicyclic ring systems contain from seven to twelve ring carbon atoms, from one to four of which may optionally be replaced with O, N or S; and wherein any of the aryl, heteroaryl or heterocyclic moieties of R¹ may optionally be substituted with from one to three substitutuents, preferably with one or two substutituents, independently selected from halo (i.e., chloro, fluoro, bromo or iodo), (C₁-C₆)alkyl optionally substituted with from one to seven (preferably with from zero to four) fluorine atoms, phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro, (C₁-C₆)alkoxy, (C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂amino, and wherein any of the alkyl moieties in R¹ (e.g., the alkyl moieties of alkyl, alkoxy or alkylamino groups) may optionally be substituted with from one to seven (preferably with from zero to four) fluorine atoms; R² is hydrogen, aryl, heteroaryl, heterocyclic, SO₂R⁴, COR⁴, CONR⁵R⁶, COOR⁴, or C(OH)R⁵R⁶ wherein each of R⁴, R⁵ and R⁶ is defined, independently, as R¹ is defined above, or R⁵ and R⁶, together with the carbon or nitrogen to which they are both attached, form a three to seven membered saturated ring containing from zero to three heterocarbons selected, independently, from O, N and S, and wherein said aryl, heteroaryl, and heterocyclic are defined as such terms are defined above in the definition of R¹, and wherein any of the aryl, heteroaryl and heterocyclic moieties of R² may optionally be substituted with from one to three substitutuents, preferably with one or two substutituents, independently selected from halo (i.e., chloro, fluoro, bromo or iodo), (C₁-C₆)alkyl optionally substituted with from one to seven (preferably with from zero to four) fluorine atoms, phenyl, benzyl, hydroxy, acetyl, amino, cyano, nitro, (C₁-C₆)alkoxy optionally substituted with from one to seven (preferably with from zero to four) fluorine atoms, (C₁-C₆)alkylamino and [(C₁-C₆)alkyl]₂amino; R³ is hydroxy, —NHSO₂R⁷, —C(OH)R⁷R⁸, —OC(═O)R⁷, fluorine or —CONHR⁷, wherein R⁷ and R⁸ are the same or different and are selected from hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy and (C₁-C₄)alkoxy-(C₁-C₄)alkyl having a total of four or less carbon atoms, and wherein any of the alkyl moieties of R⁷ and R⁸ may optionally be substituted with from one to seven (preferably with from zero to four) fluorine atoms; Q is oxygen or CH₂; X is CH or N; and Z¹ and Z² are selected, independently, from hydrogen, halo and (C₁-C₅)alkyl; with the proviso that there are no two adjacent ring oxygen atoms and no ring oxygen atom adjacent to either a ring nitrogen atom or a ring sulfur atom in any of the heterocyclic or heteroaryl moieties of formula I; or a pharmaceutically acceptable salt of such compound.
 2. A compound according to claim 1 wherein Q is CH₂.
 3. A compound according to claim 1 wherein X is CH.
 4. A compound according to claim wherein X is N.
 5. A compound according to claim 1 wherein Q is oxygen.
 6. A compound according to claim 1 wherein R³ is OH, CONH₂, or fluoro.
 7. A compound according to claim 1 wherein R² is selected from C(OH)(C₂H₆)₂, CONCH₃(CH₂CH₃), CON(C₂H₆)₂ and the following cyclic groups:


8. A compound according to claim 2 wherein X is CH.
 9. A compound according to claim 2 wherein X is N.
 10. A compound according to claim 6 wherein Q is CH₂ and X is CH.
 11. A compound according to claim 7 wherein Q is CH₂ and X is CH.
 12. A compound according to claim 6 wherein Q is CH₂ and X is N.
 13. A compound according to claim 7 wherein Q is CH₂ and X is N.
 14. A pharmaceutical composition for treating a disorder or condition selected from inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, disorders of respiratory function such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhoea, functional distension, functional pain, nonulcerogenic dyspepsia and other disorders of motility or secretion, and emesis, stroke, shock, brain edema, head trauma, spinal cord trauma, cerebral ischemia, cerebral deficits subsequent to cardiac bypass surgery and grafting, urogential tract disorders such as urinary incontinence, chemical dependencies and addictions (e.g., addictions to or dependencies on alcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), chronic pain, nonsomatic pain, acute pain and neurogenic pain, systemic lupus erythematosis, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts in a mammal, comprising an amount of a compound according to claim 1 that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier.
 15. A pharmaceutical composition for treating a disorder or condition, the treatment or prevention of which can be effected or facilitated by modulating binding to opioid receptors in a mammal, comprising an amount of a compound according to claim 1 that is effective in treating such disorder or condition and a pharmaceutically acceptable carrier.
 16. A method for treating a disorder or condition selected from inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, disorders of respiratory function such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhoea, functional distension, functional pain, nonulcerogenic dyspepsia and other disorders of motility or secretion, and emesis, stroke, shock, brain edema, head trauma, spinal cord trauma, cerebral ischemia, cerebral deficits subsequent to cardiac bypass surgery and grafting, urogential tract disorders such as urinary incontinence, chemical dependencies and addictions (e.g., addictions to or dependencies on alcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), chronic pain, nonsomatic pain, acute pain and neurogenic pain, systemic lupus erythematosis, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts in a mammal, comprising administering to a mammal requiring such treatment an amount of a compound according to claim 1 that is effective in treating such disorder or condition.
 17. A method for treating a disorder or condition, the treatment of which can be effected or facilitated by modulating binding to opioid receptors in a mammal, comprising administering to a mammal requiring such treatment an amount of a compound according to claim 1 that is effective in treating such disorder or condition.
 18. A pharmaceutical composition for treating a disorder or condition selected from inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, disorders of respiratory function such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhoea, functional distension, functional pain, nonulcerogenic dyspepsia and other disorders of motility or secretion, and emesis, stroke, shock, brain edema, head trauma, spinal cord trauma, cerebral ischemia, cerebral deficits subsequent to cardiac bypass surgery and grafting, urogential tract disorders such as urinary incontinence, chemical dependencies and addictions (e.g., addictions to or dependencies on alcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), chronic pain, nonsomatic pain, acute pain and neurogenic pain, systemic lupus erythematosis, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts in a mammal, comprising an opioid receptor binding modulating effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
 19. A pharmaceutical composition for treating a disorder or condition, the treatment or prevention of which can be effected or facilitated by modulating binding to opioid receptors in a mammal, comprising an opioid receptor binding modulating effective amount of a compound according to claim I and a pharmaceutically acceptable carrier.
 20. A method for treating a disorder or condition selected from inflammatory diseases such as arthritis, psoriasis, asthma, or inflammatory bowel disease, disorders of respiratory function such as asthma, cough and apnea, allergies, gastrointestinal disorders such as gastritis, functional bowel disease, irritable bowel syndrome, functional diarrhoea, functional distension, functional pain, nonulcerogenic dyspepsia and other disorders of motility or secretion, and emesis, stroke, shock, brain edema, head trauma, spinal cord trauma, cerebral ischemia, cerebral deficits subsequent to cardiac bypass surgery and grafting, urogential tract disorders such as urinary incontinence, chemical dependencies and addictions (e.g., addictions to or dependencies on alcohol, opiates, benzodiazepines, nicotine, heroin or cocaine), chronic pain, nonsomatic pain, acute pain and neurogenic pain, systemic lupus erythematosis, Hodgkin's disease, Sjogren's disease, epilepsy and rejection in organ transplants and skin grafts in a mammal, comprising administering to a mammal requiring such treatment an opioid receptor binding modulating effective amount of a compound according to claim
 1. 21. A method for treating a disorder or condition, the treatment or prevention of which can be effected or facilitated by modulating binding to opioid receptors in a mammal, comprising administering to a mammal requiring such treatment an opioid receptor binding modulating effective amount of a compound according to claim
 1. 